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Diabetic angiopathy and angiogenic defects

Abstract

Diabetes is one of the most serious health problems in the world. A major complication of diabetes is blood vessel disease, termed angiopathy, which is characterized by abnormal angiogenesis. In this review, we focus on angiogenesis abnormalities in diabetic complications and discuss its benefits and drawbacks as a therapeutic target for diabetic vascular complications. Additionally, we discuss glucose metabolism defects that are associated with abnormal angiogenesis in atypical diabetic complications such as cancer.

Review

The epidemic of obesity-associated type 2 diabetes has prompted the need for strategies to prevent and treat diabetic complications [1]. In diabetes, diverse sets of organs are damaged. Such organ damage is certainly fundamentally associated with glucose metabolism defects. Therefore, normalizing blood glucose levels is essential for diabetic therapy [2–4]. However, recent evidence suggests that normalization of blood glucose levels is challenging in diabetes, and such intensive therapies in diabetic patients are associated with increased mortality risk, likely associated with frequent hypoglycemia [5]. To this end, patients enrolled in the intensive therapy group of the ACCORD trial, which employed intensive blood glucose lowering strategies aimed to normalize blood sugar levels, exhibited increased mortality [5]. Therefore, to prevent diabetic complications, additional therapeutic strategies are required in addition to those that target blood glucose normalization.

Angiopathy is a term for vascular defects that are associated with angiogenic abnormalities [6]. Understanding the precise molecular mechanisms that lead to diabetic angiopathy is essential for designing new therapeutic strategies to treat diabetic complications. In this review, we focus on diabetic vascular defects and abnormal angiogenesis.

Angiogenesis

Angiogenesis is characterized by new blood vessel formation from pre-existing vessels and is distinguished from vasculogenesis, which is de novo vessel formation from hematopoietic progenitor cells [7]. Angiogenesis is essential for proper development and organ homeostasis, such as placental and embryonic growth, collateral formation, wound healing, and granulation [8]. However, angiogenesis is not always healthy and is often associated with pathologic conditions, in which case it is referred to as pathologic angiogenesis [7]. Angiogenesis results from the balanced functions of pro- and anti-angiogenic molecules (Figure 1). Defects in the angiogenic balance may cause a shift towards either excessive or anti-angiogenesis. Among angiogenic regulators, vascular endothelial growth factor (VEGF) has been associated with several diabetic complications, particularly diabetic retinopathy.

Figure 1
figure 1

Schematic image of angiogenesis switch. Angiogenesis results from the balanced functions of pro-angiogenic and anti-angiogenic molecules. Defects in the angiogenic balance lead to a shift toward either excessive angiogenesis or anti-angiogenesis. CSF, colony-stimulating factor; EGF, epidermal growth factor; FGF, fibroblast growth factor; FLT1, fms-related tyrosine kinase 1; HGF, hepatocyte growth factor; IGF, insulin-like growth factor; MMP, matrixmetalloproteinases, PDGF, platelet-derived growth factor; PECAM-1, platelet endothelial cell adhesion molecular (also known as CD31); PEDF, pigment epithelium-derived factor; TGFβ, transforming growth factor-β; TIMP, tissue inhibitor of metalloproteinases; TNFa, tumor necrosis factor-α; VE, vascular endothelial; VEGF, vascular endothelial growth factor.

In diabetes, angiogenesis is regulated in an organ-, tissue-, and cell type-specific manner [9]. For example, in the retina, VEGF likely plays pro-angiogenic roles; thus, neutralizing VEGF is one anti-angiogenesis therapeutic strategy that is currently employed in clinical settings [10, 11]. However, in the diabetic heart, VEGF signals are disturbed and collateral vessel formation is disrupted in spite of VEGF levels that are similar to those in non-diabetic subjects [12]. In cancer cells, high glucose induces the accumulation of hypoxia inducible factor (HIF)-1α and the associated expression of VEGF; however, in normal cells, such exposure to high glucose inhibits HIF-1α and VEGF expression [13, 14].

Abnormal angiogenesis and diabetic retinopathy

The abnormal angiogenesis that occurs in diabetic retinopathy has been well characterized. In diabetic retinopathy, the pericytes of the retinal capillaries are injured, which is associated with defective capillary function [15–19]. Such capillary deficiency is associated with defects in proper oxygen delivery and nutrient supply, resulting in VEGF overproduction in the retina [17]. This VEGF overproduction is also associated with abnormal angiogenesis and enhanced retinal capillary permeability, resulting in retinal dysfunction associated with the loss of visual acuity in these patients [17–19]. One therapeutic approach for diabetic retinopathy, light coagulation, has been performed for several years in clinical settings; however, this treatment is insufficient by itself.

In the ocular system, VEGF signaling is strictly regulated. For example, the cornea is an avascular organ, and this lack of vascularity is regulated by abundant soluble VEGF receptor 1 (also known as sFlt1), which is a secreted protein that binds and sequesters VEGF from the VEGF receptors on the cell surface (Figure 2) [20]. The only mammal with a vascularized cornea is the manatee, which is due to a lack of corneal sFlt1 [20]. These properties of VEGF have enabled scientists to design molecules that target and normalize VEGF signaling using similar mechanisms to sFlt1, the endogenous VEGF blocker (Figure 2). Therefore, anti-VEGF molecules, such as pegaptanib sodium (Macugen), ranibizumab (Lucentis), and bevacizumab (Avastin) have been developed.

Figure 2
figure 2

sFllt1 plays as endogenous inhibitor of VEGF signaling by trapping free-VEGF. VEGF signaling is strictly regulated by endogenous molecules, including sFlt1. sFlt1 binds to and sequesters VEGF from cell-surface VEGF receptors, subsequently VEGF modulated pro-angiogenesis signal is inhibited.

In 2004, the U.S. Food and Drug Administration (FDA) approved pegaptanib sodium for the treatment of age-related macular degeneration, in which abnormal VEGF signals are associated with abnormal angiogenesis and edema in the retina, similar to diabetic retinopathy [21]. Pegaptanib sodium was the first anti-VEGF drug approved for ocular disease. This provided seminal evidence that VEGF is responsible for the ocular diseases that are associated with abnormal angiogenesis [22]. In later clinical trials, ranibizumab was shown to be effective in more than 90% of the cases of age-related macular degeneration [23, 24]. The FDA has approved bevacizumab to treat colorectal cancer, but it has not been approved for the treatment of ocular diseases; however, this drug is being tested clinically for treating age-related macular degeneration [25]. Anti-VEGF therapy is also effective for diabetic retinopathy [10], indicating a critical role for VEGF in the pathogenesis of this disease.

Abnormal angiogenesis and diabetic nephropathy

Diabetic nephropathy is the leading cause of end-stage renal disease worldwide. The number of patients requiring hemodialysis because of diabetic kidney-associated diseases has increased tremendously over the past two decades. Once renal function has deteriorated, many associated cardiovascular events can occur [26–28]. Therefore, more research is needed to discover novel strategies to prevent or slow this decline in renal function. Furthermore, the therapeutic targeting of angiogenic abnormalities provides substantial clinical benefits. However, the contribution of VEGF to diabetic nephropathy-induced angiogenesis is complicated.

First, we review VEGF biology in the normal kidney, which is based on the experiences of cancer patients that have been treated with bevacizumab [29]. These patients displayed hypertension, edema, proteinuria, and glomerular capillary damage [30–32]. Similar renal microcirculation effects have been reported in rodents after human sFlt1 injection [33], adenovirus-mediated humans Flt1 overexpression [34], or endothelial specific VEGF deletion, which induced endothelial damage with microthrombi [35]. It is also hypothesized that the actions of anti-VEGF molecules might be associated with microcirculation injuries that occur in pre-eclampsia patients [34, 36, 37]. Therefore, VEGF is essential for the homeostatic maintenance of renal hemodynamics. In contrast, VEGF overproduction in the glomerular podocytes is associated with glomerular capillary collapse and HIV-associated glomerulopathy [38, 39].

In diabetic nephropathy, abnormal angiogenesis in the glomeruli, as well as VEGF overexpression, has been reported, similar to diabetic retinopathy [40, 41]. The properties of these abnormal vessels and how these vessels are associated with the pathogenesis of diabetic nephropathy are not well described. In experimental animal models, anti-VEGF therapy [41–44] or administering anti-angiogenesis molecules [45–49] may reverse such abnormal angiogenesis in diabetic kidneys, concomitantly reducing albumin excretion into the urine. However, recent evidence suggests that the neutralization of VEGF by sFlt1 in diabetic animal models ameliorates abnormal vasculature in the glomeruli, but in the interstitium, sFlt1-mediated VEGF neutralization caused the deterioration of pathological lesions [50]. These data demonstrate the complexity of the VEGF overproduction-associated angiogenic pathways in diabetic kidneys. Therefore, angiogenesis abnormalities in diabetic nephropathy progression are still controversial, and further research needs to be conducted to determine whether, and how, abnormal angiogenesis can be therapeutically targeted.

Abnormal angiogenesis and atherosclerosis

Atherosclerosis-associated coronary artery disease is a major cause of mortality in diabetic patients. It is likely that plaques, the core atherosclerotic lesions, play essential roles in the onset of life-threatening coronary artery disease. The plaque begins as a fatty streak, an ill-defined yellow lesion-fatty plaque, which develops well-demarcated edges, and evolves to fibrous plaques, which are whitish lesions with a grumous lipid-rich core [51]. The rupture of these plaques following the enlargement of the necrotic core is associated with luminal thrombosis in acute coronary syndrome, which occurs in 75% of patients who die of an acute myocardial infarction [52]. However, the mechanisms by which asymptomatic fibroatheromatous plaques progress to high-risk, unstable lesions are not clear.

Intra-plaque hemorrhage may play an important role in the process of plaque destabilization [53]. Red blood cell (RBC) membranes are rich in phospholipids and free cholesterol, and RBC accumulation within the plaques plays an important role in the progression of plaque instability [54]. The RBC source within the coronary lesions is therefore important, and it is likely that leaky, immature vessels within the plaque allow the entry of RBCs into the lesions [54]. In the unstable or ruptured plaque, newly formed vessels are found in abundance [54]. Pathologic examination of unstable lesions has demonstrated that intraplaque hemorrhage and plaque rupture are associated with increased microvessel density. Although most intraplaque vasa vasorum are endothelialized, only a few have mural cells such as pericytes and vascular smooth muscle cells [55, 56]. This lack of mural cells may contribute to vessel leakiness because such vessels are fragile and are therefore easily damaged. This damage results in the development of immature vessels within the lesion, which are associated with abnormal angiogenesis [57].

During plaque progression, the plaque becomes complicated and is composed of infiltrated inflammatory cells, smooth muscle cells, and extracellular matrix in the large artery intima [57]. Inflammatory cells such as T-cells and macrophages may contribute to VEGF production within the lesion [57]. Plaque progression may be associated with decreased oxygen and nutrient supply within the lesion [58–60], which directly leads to HIF-1α accumulation and the subsequent induction of pro-angiogenic molecules. Therefore, inflammation and hypoxia within plaque lesions could activate angiogenesis and contribute to the plaque instability that is associated with abnormal angiogenesis.

Wound healing defects in diabetes and angiogenesis

Wound healing capacity in diabetic patients is decreased. The normal process of wound healing is characterized by five sequential processes: (1) hemostasis, (2) inflammation and debridement, (3) proliferation, (4) epithelialization, and (5) remodeling [61]. The delayed wound healing in diabetic patients has been attributed to disturbances in the inflammation/debridement and proliferation phases [61, 62]. In the wound healing process, microangiopathy may also contribute to defects in the nutrient/oxygen supply, thus inhibiting normal healing processes [63]. Both clinical research and animal models have confirmed such wound healing defects in diabetes.

In diabetic patients, chronic non-healing ulcers are frequently observed at pressure points of the lower extremities [62]. Pathological analysis has revealed abnormal microvessels that can be cuffed with collagen, laminin, fibronectin, or fibrin in the wound edges of these diabetic ulcers [64]. Fibroblasts isolated from diabetic ulcers display diminished proliferative capacity and abnormal morphological features, such as multiple lamellar and vesicular bodies, an absence of microtubular structures, and enlarged, dilated endoplasmic reticulum, indicative of a hypertrophic phenotype [61]. Such alterations would be functionally relevant to angiogenic defects within the wound because fibroblasts play essential angiogenic roles by producing several pro-angiogenic cytokines such as VEGF and fibroblast growth factors [65], and because microtubules are important for fibroblast migration [66, 67].

Another possible cause of wound healing defects in diabetes patients has been associated with altered biology of bone marrow-derived endothelial progenitor cells (EPCs) [68, 69]. EPCs are thought to be essential in vasculogenesis and wound healing, but their functions and numbers in the circulation and within wounds have been shown to be compromised in diabetic patients [68–75]. Defects in the recruitment of EPCs for re-endothelialization has been suggested in diabetes patients [76]. VEGF signaling, matrix metalloproteinases, and endothelial nitric oxide synthase (eNOS) have been shown to play essential roles for the recruitment of EPCs into wounds [77, 78]. Recently, Albiero et al.. showed that EPCs in diabetic patients exhibited both proliferative defects and enhanced apoptosis without altering the number of circulating EPCs [79], suggesting that diabetes affects EPC survival signaling, and such a survival defect could be a potential therapeutic target for treating defects in diabetic wound healing.

Abnormal angiogenesis and cancer

Diabetes increases mortality risk in cancer patients [80, 81]. Cancer patients who already have diabetes reportedly have a greater chance of dying of the cancer than those who do not [80]. Furthermore, cancer patients with preexisting diabetes exhibit approximately a 50% greater risk of dying after surgery [81]. There are many theories for this diabetes-associated increase in mortality, such as possible links to glucose-mediated cancer growth, immunodeficiency, infections, or other health problems. Diabetes is also associated with the diagnosis of more advanced cancers [82]. Therefore, there are possible links between cancer-accelerating factors and diabetes.

Several clinical trials have demonstrated that anti-angiogenesis therapy is beneficial for cancer treatment [83], suggesting that increased angiogenic signals contribute to cancer progression. Tumor hypoxia is a strong angiogenesis inducer via accumulation of HIFs and their downstream targets, such as VEGF. These angiogenic abnormalities may be relevant to the association between cancer and diabetes. In tumor cells, high levels of glucose induce the accumulation and expression of HIF-1α, whereas non-tumor cells exhibit decreased HIF-1α accumulation in response to high glucose [13, 14], suggesting that impaired glucose homeostasis directly affects angiogenic signals within tumors.

Type 2 diabetes is characterized by insulin resistance and hyperinsulinemia. Hyperinsulinemia induces breast cancer development in experimental animal models [84]. Type 2 diabetes is often associated with obesity, which is another risk factor for cancer [85]. Additionally, patients with type 2 diabetes exhibit increased levels of insulin-like growth factor (IGF)-1, a potent mitogen and pro-angiogenic factor that may contribute to carcinogenesis [86]. IGF-1 promotes liver metastasis in xenograft colon adenocarcinoma models in obese mice [87]. Furthermore, insulin resistance in type 2 diabetes is associated with diacylglycerol (DAG) accumulation in cells [88, 89]. DAG accumulation can cause activation of the protein kinase C family of serine-threonine kinases [89], which play important roles in cancer biology and abnormal angiogenesis in diabetic patients [90].

In cancer biology, angiogenesis is closely connected with inflammation [91, 92]. Recently, Park et al. reported that enhanced inflammation in obesity is associated with liver carcinogenesis [93]. They used leptin-deficient ob/ob mice and high-fat diet (59% fat, 15% protein, 26% carbohydrate)-induced obesity models and found that diethylnitrosamine-induced hepatocellular carcinoma (HCC) is significantly advanced in the both of these murine obesity models [93]. The high-fat diet also resulted in increased growth of subcutaneous-injected HCC [93]. The mechanisms of obesity-induced liver carcinogenesis were found to be associated with hepatic activation of the Stat signaling pathway and inflammation [93]. To this end, depleting inflammatory cytokines interleukin-6 or tumor necrosis factor-α in the liver of obese mice abolished the tumor-promoting effect of obesity, thus suggesting a critical role of inflammation in obesity-associated carcinogenesis [93].

Leptin levels are often elevated in obesity-induced type 2 diabetes, which could be another possible connection to abnormal angiogenesis and cancer. Leptin induced endothelial cell proliferation both in vivo and in vitro[94]. Using androgen-insensitive murine prostate carcinoma RM1 cells, Ribeiro et al. recently reported that ob/ob mice, which lack leptin, and diet-induced obese mice exhibited large tumors. Conversely, db/db mice, which express leptin but have a mutation in the leptin receptor, displayed small tumors, suggesting that leptin has a tumor-suppressive role [95]. However, Gonzalez et al. reported that leptin may accelerate murine breast tumor growth because it induces VEGF-mediated angiogenesis [96], even though the mouse model used in this study was the immunodeficient SCID mouse, which is neither diabetic nor obese [97]. Similarly, leptin induced proliferation and invasiveness of endometrial cancer cells [98]. Recently, Bartucci et al. found that the leptin receptor is expressed on colorectal cancer stem cells; therefore, leptin may induce tumor growth and interferes with the cytotoxic effects of the anti-cancer drug 5-FU [99].

Diabetes in pregnancy and vascular defects of the embryo and placenta

The vasculature is the first embryonic system to develop and is vulnerable to insults from the uterine environment. Hyperglycemia is associated with embryonic vasculopathy, which may lead to embryonic lethality or malformation [100–106]. The molecular mechanisms underlying maternal diabetes-induced embryonic vasculopathy are unclear. Several in-vitro and ex-vivo studies suggest that exposure to high glucose induces anomalies in the yolk sac microvasculature [107, 108]. Embryos in streptozotocin-injected pregnant female mice exhibit abnormal angiogenesis and vasculogenesis [108]. Recently, Yang et al. reported that decreased accumulation of HIF-1α in the conceptus when cultured in high-glucose media might be associated with decreased VEGF, thus suggesting that HIF-1α homeostasis may be the key to understanding embryonic diabetes-induced vasculopathy [109].

Developing the placental vasculature is essential for the developmental homeostasis of the placenta and fetus. Defects in the placental vasculature are associated with placental hypoxia, which may result in the onset of pre-eclampsia [110], the devastating pregnancy-associated hypertensive syndrome. Maternal hyperglycemia, caused by either pre-existing or pregnancy-induced diabetes, has been associated with increased incidence of placental defects and pre-eclampsia. Morphologically, diabetic pregnancy is characterized by reduced fetal capillary branching, maldevelopment of the villous tree, and impaired adaptation of maternal vasculature during pregnancy [111–117]. Diabetic mothers without pre-eclampsia tend to have decreased levels of pro-angiogenic molecules [118]. However, the poor development of the placental vasculature in pre-eclampsia is most likely not a result of imbalance among VEGF signaling pathways, but rather of complex interactions among maternal spiral arteries and the trophoblast [110, 119–121]. Inflammation in the maternal-fetal interface is also essential for development of the placental vasculature [122–125]. Therefore, all of these molecules may be relevant in the placental and embryonic angiogenesis defects that occur in diabetic pregnancies. These points should be clarified by further research.

Perspective

In this review, we summarized and discussed diabetic angiopathy while focusing on angiogenic defects. Systemic angiogenesis modification therapies that either inhibit or activate angiogenesis are not acceptable therapeutic strategies because of the potential adverse reactions that may occur. Therefore, there is a need to target locally acting molecules, such as VEGF, to treat diabetic retinopathy. To this end, inhibition of ocular VEGF has emerged as a promising treatment modality for diabetic retinopathy and is currently being evaluated in clinical trials. However, anti-VEGF therapy for the treatment of diabetic retinopathy is of limited use and involves potential adverse reactions such as retinal ischemia, vasoconstriction, inflammation or detachment [126–131]. Another possible strategy for treating VEGF-mediated angiogenesis defects could be to target mediators of VEGF intracellular signaling pathways such as phosphoinositide 3-kinase, Akt, protein-kinase C, mitogen activated protein kinases, or nitric oxide. However, avoiding potential adverse effects would be essential and tissue specificity could be an important issue.

We focused on the role of the VEGF system in diabetic angiopathy and angiogenetic defects in this review. However, other molecules contribute to abnormal angiogenesis in diabetes. As shown in Figure 1, various pro- and anti-angiogenic molecules could be relevant in the pathogenesis of diabetes-induced angiogenesis defects. The role of fibroblast growth factors and angiopoietins in the onset of diabetic nephropathy and/or retinopathy has been previously demonstrated [132]. A potential for targeting several other endogenous anti-angiogenic factors such as platelet factor-4, angiostatin, endostatin, vasostatin, and tumstatin has also been described for preclinical diabetic angiopathy treatment [132]. These are all potent, significant molecules, and further research is required to determine how these findings can be applied in clinical settings.

Conclusion

In diabetes, the VEGF response likely depends on the cell type and organ (Figure 3). Additionally, hypoxic responses and the induction of the master hypoxia transcription factor, HIF-1α, depends on the cell type [13, 14]. Altered angiogenesis is a well-defined pathogenesis of diabetic angiopathy, although to therapeutically target angiogenesis defects, further research to identify tissue, organ, and disease-specific molecules is necessary.

Figure 3
figure 3

The biology of angiogenesis abnormality in diabetic organ dysfunction. In diabetes, the angiogenesis signal is regulated in an organ-, tissue-, and cell type-specific manner. In the retina, atherosclerotic plaque, kidney glomerulus, and cancer, VEGF likely plays pro-angiogenic roles; on the contrary, in diabetic heart, kidney tubule, peripheral vessels, and placenta, VEGF signal is inhibited.

Abbreviations

ACCORD:

Action to Control Cardiovascular Risk in Diabetes

eNOS:

Endothelial Nitric Oxide Synthase

EPC:

Endothelial progenitor cells

HIF-1α:

Hypoxia inducible factor-1α

IGF:

Like growth factor

sFlt1:

Soluble fms-like tyrosine kinase-1 (same as VEGF type1 receptor)

VEGF:

Vascular endothelial growth factor.

References

  1. Kopelman P: Health risks associated with overweight and obesity. Obes Rev. 2007, Suppl 1: 13-17.

    Article  Google Scholar 

  2. The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993, 329: 977-986.

    Article  Google Scholar 

  3. UK Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998, 352: 854-865.

    Article  Google Scholar 

  4. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M: Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract. 1995, 28: 103-117. 10.1016/0168-8227(95)01064-K.

    Article  CAS  PubMed  Google Scholar 

  5. Ismail-Beigi F, Craven T, Banerji MA, Basile J, Calles J, Cohen RM, Cuddihy R, Cushman WC, Genuth S, Grimm RH, Hamilton BP, Hoogwerf B, Karl D, Katz L, Krikorian A, O’Connor P, Pop-Busui R, Schubart U, Simmons D, Taylor H, Thomas A, Weiss D, Hramiak I, for the ACCORD trial group: Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet. 2010, 376: 419-430. 10.1016/S0140-6736(10)60576-4.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Martin A, Komada MR, Sane DC: Abnormal angiogenesis in diabetes mellitus. Med Res Rev. 2003, 23: 117-145. 10.1002/med.10024.

    Article  CAS  PubMed  Google Scholar 

  7. Nyberg P, Xie L, Kalluri R: Endogenous inhibitors of angiogenesis. Cancer Res. 2005, 65: 3967-3979. 10.1158/0008-5472.CAN-04-2427.

    Article  CAS  PubMed  Google Scholar 

  8. Folkman J: Angiogenesis: an organizing principle for drug discovery?. Nat Rev Drug Discov. 2007, 6: 273-286. 10.1038/nrd2115.

    Article  CAS  PubMed  Google Scholar 

  9. Waltenberger J: VEGF resistance as a molecular basis to explain the angiogenesis paradox in diabetes mellitus. Biochem Soc Trans. 2009, 37: 1167-1170. 10.1042/BST0371167.

    Article  CAS  PubMed  Google Scholar 

  10. Rishi P, Bhende PS: Images in clinical medicine. Proliferative diabetic retinopathy. N Engl J Med. 2009, 360: 912-10.1056/NEJMicm0708063.

    Article  CAS  PubMed  Google Scholar 

  11. Smith JM, Steel DH: Anti-vascular endothelial growth factor for prevention of postoperative vitreous cavity haemorrhage after vitrectomy for proliferative diabetic retinopathy. Cochrane Database Syst Rev. 2011, 5: CD008214.

    PubMed  Google Scholar 

  12. Sasso FC, Torella D, Carbonara O, Ellison GM, Torella M, Scardone M, Marra C, Nasti R, Marfella R, Cozzolino D, Indolfi C, Cotrufo M, Torella R, Salvatore T: Increased vascular endothelial growth factor expression but impaired vascular endothelial growth factor receptor signaling in the myocardium of type 2 diabetic patients with chronic coronary heart disease. J Am Coll Cardiol. 2005, 46: 827-834. 10.1016/j.jacc.2005.06.007.

    Article  CAS  PubMed  Google Scholar 

  13. Dehne N, Hintereder G, Brune B: High glucose concentrations attenuate hypoxia-inducible factor-1alpha expression and signaling in non-tumor cells. Exp Cell Res. 2010, 316: 1179-1189. 10.1016/j.yexcr.2010.02.019.

    Article  CAS  PubMed  Google Scholar 

  14. Lu H, Dalgard CL, Mohyeldin A, McFate T, Tait AS, Verma A: Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1. J Biol Chem. 2005, 280: 41928-41939. 10.1074/jbc.M508718200.

    Article  CAS  PubMed  Google Scholar 

  15. Pfister F, Feng Y, vom Hagen F, Hoffmann S, Molema G, Hillebrands JL, Shani M, Deutsch U, Hammes HP: Pericyte migration: a novel mechanism of pericyte loss in experimental diabetic retinopathy. Diabetes. 2008, 57: 2495-2502. 10.2337/db08-0325.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Crawford TN, Alfaro DV, Kerrison JB, Jablon EP: Diabetic retinopathy and angiogenesis. Curr Diabetes Rev. 2009, 5: 8-13. 10.2174/157339909787314149.

    Article  CAS  PubMed  Google Scholar 

  17. Kermorvant-Duchemin E, Sapieha P, Sirinyan M, Beauchamp M, Checchin D, Hardy P, Sennlaub F, Lachapelle P, Chemtob S: Understanding ischemic retinopathies: emerging concepts from oxygen-induced retinopathy. Doc Ophthalmol. 2010, 120: 51-60. 10.1007/s10633-009-9201-x.

    Article  PubMed  Google Scholar 

  18. Sapieha P, Hamel D, Shao Z, Rivera JC, Zaniolo K, Joyal JS, Chemtob S: Proliferative retinopathies: angiogenesis that blinds. Int J Biochem Cell Biol. 2010, 42: 5-12. 10.1016/j.biocel.2009.10.006.

    Article  CAS  PubMed  Google Scholar 

  19. Sapieha P, Joyal JS, Rivera JC, Kermorvant-Duchemin E, Sennlaub F, Hardy P, Lachapelle P, Chemtob S: Retinopathy of prematurity: understanding ischemic retinal vasculopathies at an extreme of life. J Clin Invest. 2010, 120: 3022-3032. 10.1172/JCI42142.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Ambati BK, Nozaki M, Singh N, Takeda A, Jani PD, Suthar T, Albuquerque RJ, Richter E, Sakurai E, Newcomb MT, Kleinman ME, Caldwell RB, Lin Q, Ogura Y, Orecchia A, Samuelson DA, Agnew DW, St Leger J, Green WR, Mahasreshti PJ, Curiel DT, Kwan D, Marsh H, Ikeda S, Leiper LJ, Collinson JM, Bogdanovich S, Khurana TS, Shibuya M, Baldwin ME, et al: Corneal avascularity is due to soluble VEGF receptor-1. Nature. 2006, 443: 993-997. 10.1038/nature05249.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Administration USFD: FDA Approves New Drug Treatment for Age-Related Macular Degeneration. FDA NEWS RELEASE. 2004, P04-110.

    Google Scholar 

  22. Fine SL, Martin DF, Kirkpatrick P: Pegaptanib sodium. Nat Rev Drug Discov. 2005, 4: 187-188. 10.1038/nrd1677.

    Article  CAS  PubMed  Google Scholar 

  23. Abraham P, Yue H, Wilson L: Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER study year 2. Am J Ophthalmol. 2010, 150: 315-324. 10.1016/j.ajo.2010.04.011. e311

    Article  CAS  PubMed  Google Scholar 

  24. Regillo CD, Brown DM, Abraham P, Yue H, Ianchulev T, Schneider S, Shams N: Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol. 2008, 145: 239-248. 10.1016/j.ajo.2007.10.004.

    Article  CAS  PubMed  Google Scholar 

  25. Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ: Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011, 364: 1897-1908.

    Article  CAS  PubMed  Google Scholar 

  26. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR: Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int. 2003, 63: 225-232. 10.1046/j.1523-1755.2003.00712.x.

    Article  PubMed  Google Scholar 

  27. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O: Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003, 348: 383-393. 10.1056/NEJMoa021778.

    Article  PubMed  Google Scholar 

  28. Gaede P, Lund-Andersen H, Parving HH, Pedersen O: Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008, 358: 580-591. 10.1056/NEJMoa0706245.

    Article  CAS  PubMed  Google Scholar 

  29. Eremina V, Jefferson JA, Kowalewska J, Hochster H, Haas M, Weisstuch J, Richardson C, Kopp JB, Kabir MG, Backx PH, Gerber HP, Ferrara N, Barisoni L, Alpers CE, Quaggin SE: VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med. 2008, 358: 1129-1136. 10.1056/NEJMoa0707330.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Izzedine H, Rixe O, Billemont B, Baumelou A, Deray G: Angiogenesis inhibitor therapies: focus on kidney toxicity and hypertension. Am J KidneyDis. 2007, 50: 203-218. 10.1053/j.ajkd.2007.04.025.

    Article  CAS  Google Scholar 

  31. Wu S, Kim C, Baer L, Zhu X: Bevacizumab increases risk for severe proteinuria in cancer patients. J Am Soc Nephrol. 2010, 21: 1381-1389. 10.1681/ASN.2010020167.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Zhu X, Wu S, Dahut WL, Parikh CR: Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis. 2007, 49: 186-193. 10.1053/j.ajkd.2006.11.039.

    Article  CAS  PubMed  Google Scholar 

  33. Sugimoto H, Hamano Y, Charytan D, Cosgrove D, Kieran M, Sudhakar A, Kalluri R: Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria. J Biol Chem. 2003, 278: 12605-12608. 10.1074/jbc.C300012200.

    Article  CAS  PubMed  Google Scholar 

  34. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi SA: Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003, 111: 649-658.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Lee S, Chen TT, Barber CL, Jordan MC, Murdock J, Desai S, Ferrara N, Nagy A, Roos KP, Iruela-Arispe ML: Autocrine VEGF signaling is required for vascular homeostasis. Cell. 2007, 130: 691-703. 10.1016/j.cell.2007.06.054.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA: Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004, 350: 672-683. 10.1056/NEJMoa031884.

    Article  CAS  PubMed  Google Scholar 

  37. Levine RJ, Thadhani R, Qian C, Lam C, Lim KH, Yu KF, Blink AL, Sachs BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA: Urinary placental growth factor and risk of preeclampsia. JAMA. 2005, 293: 77-85. 10.1001/jama.293.1.77.

    Article  CAS  PubMed  Google Scholar 

  38. Veron D, Reidy KJ, Bertuccio C, Teichman J, Villegas G, Jimenez J, Shen W, Kopp JB, Thomas DB, Tufro A: Overexpression of VEGF-A in podocytes of adult mice causes glomerular disease. Kidney Int. 2010, 77: 989-999. 10.1038/ki.2010.64.

    Article  CAS  PubMed  Google Scholar 

  39. Korgaonkar SN, Feng X, Ross MD, Lu TC, D’Agati V, Iyengar R, Klotman PE, He JC: HIV-1 upregulates VEGF in podocytes. J Am Soc Nephrol. 2008, 19: 877-883. 10.1681/ASN.2007050629.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Kanesaki Y, Suzuki D, Uehara G, Toyoda M, Katoh T, Sakai H, Watanabe T: Vascular endothelial growth factor gene expression is correlated with glomerular neovascularization in human diabetic nephropathy. Am J Kidney Dis. 2005, 45: 288-294. 10.1053/j.ajkd.2004.09.020.

    Article  CAS  PubMed  Google Scholar 

  41. Tsuchida K, Makita Z, Yamagishi S, Atsumi T, Miyoshi H, Obara S, Ishida M, Ishikawa S, Yasumura K, Koike T: Suppression of transforming growth factor beta and vascular endothelial growth factor in diabetic nephropathy in rats by a novel advanced glycation end product inhibitor, OPB-9195. Diabetologia. 1999, 42: 579-588. 10.1007/s001250051198.

    Article  CAS  PubMed  Google Scholar 

  42. de Vriese AS, Tilton RG, Elger M, Stephan CC, Kriz W, Lameire NH: Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes. J Am Soc Nephrol. 2001, 12: 993-1000.

    CAS  PubMed  Google Scholar 

  43. Sung SH, Ziyadeh FN, Wang A, Pyagay PE, Kanwar YS, Chen S: Blockade of vascular endothelial growth factor signaling ameliorates diabetic albuminuria in mice. J Am Soc Nephrol. 2006, 17: 3093-3104. 10.1681/ASN.2006010064.

    Article  CAS  PubMed  Google Scholar 

  44. Chen S, Kasama Y, Lee JS, Jim B, Marin M, Ziyadeh FN: Podocyte-derived vascular endothelial growth factor mediates the stimulation of alpha3(IV) collagen production by transforming growth factor-beta1 in mouse podocytes. Diabetes. 2004, 53: 2939-2949. 10.2337/diabetes.53.11.2939.

    Article  CAS  PubMed  Google Scholar 

  45. Yamamoto Y, Maeshima Y, Kitayama H, Kitamura S, Takazawa Y, Sugiyama H, Yamasaki Y, Makino H: Tumstatin peptide, an inhibitor of angiogenesis, prevents glomerular hypertrophy in the early stage of diabetic nephropathy. Diabetes. 2004, 53: 1831-1840. 10.2337/diabetes.53.7.1831.

    Article  CAS  PubMed  Google Scholar 

  46. Ichinose K, Maeshima Y, Yamamoto Y, Kitayama H, Takazawa Y, Hirokoshi K, Sugiyama H, Yamasaki Y, Eguchi K, Makino H: Antiangiogenic endostatin peptide ameliorates renal alterations in the early stage of a type 1 diabetic nephropathy model. Diabetes. 2005, 54: 2891-2903. 10.2337/diabetes.54.10.2891.

    Article  CAS  PubMed  Google Scholar 

  47. Zhang SX, Wang JJ, Lu K, Mott R, Longeras R, Ma JX: Therapeutic potential of angiostatin in diabetic nephropathy. J Am Soc Nephrol. 2006, 17: 475-486. 10.1681/ASN.2005020217.

    Article  CAS  PubMed  Google Scholar 

  48. Wang JJ, Zhang SX, Mott R, Knapp RR, Cao W, Lau K, Ma JX: Salutary effect of pigment epithelium-derived factor in diabetic nephropathy: evidence for antifibrogenic activities. Diabetes. 2006, 55: 1678-1685. 10.2337/db05-1448.

    Article  CAS  PubMed  Google Scholar 

  49. Nasu T, Maeshima Y, Kinomura M, Hirokoshi-Kawahara K, Tanabe K, Sugiyama H, Sonoda H, Sato Y, Makino H: Vasohibin-1, a negative feedback regulator of angiogenesis, ameliorates renal alterations in a mouse model of diabetic nephropathy. Diabetes. 2009, 58: 2365-2375. 10.2337/db08-1790.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Kosugi T, Nakayama T, Li Q, Chiodo VA, Zhang L, Campbell-Thompson M, Grant M, Croker BP, Nakagawa T: Soluble Flt-1 gene therapy ameliorates albuminuria but accelerates tubulointerstitial injury in diabetic mice. Am J Physiol Renal Physiol. 2010, 298: F609-616. 10.1152/ajprenal.00377.2009.

    Article  CAS  PubMed  Google Scholar 

  51. Rosenfeld ME: An overview of the evolution of the atherosclerotic plaque: from fatty streak to plaque rupture and thrombosis. Z Kardiol. 2000, Suppl 7: 2-6.

    Google Scholar 

  52. Davies MJ, Thomas A: Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death. N Engl J Med. 1984, 310: 1137-1140. 10.1056/NEJM198405033101801.

    Article  CAS  PubMed  Google Scholar 

  53. Kolodgie FD, Gold HK, Burke AP, Fowler DR, Kruth HS, Weber DK, Farb A, Guerrero LJ, Hayase M, Kutys R, Narula J, Finn AV, Virmain R: Intraplaque hemorrhage and progression of coronary atheroma. N Engl J Med. 2003, 349: 2316-2325. 10.1056/NEJMoa035655.

    Article  CAS  PubMed  Google Scholar 

  54. Tziakas DN, Chalikias GK, Stakos D, Boudoulas H: The role of red blood cells in the progression and instability of atherosclerotic plaque. Int J Cardiol. 2010, 142: 2-7. 10.1016/j.ijcard.2009.10.031.

    Article  PubMed  Google Scholar 

  55. McCarthy MJ, Loftus IM, Thompson MM, Jones L, London NJ, Bell PR, Naylor AR, Brindle NP: Angiogenesis and the atherosclerotic carotid plaque: an association between symptomatology and plaque morphology. J Vasc Surg. 1999, 30: 261-268. 10.1016/S0741-5214(99)70136-9.

    Article  CAS  PubMed  Google Scholar 

  56. McCarthy MJ, Loftus IM, Thompson MM, Jones L, London NJ, Bell PR, Naylor AR, Brindle NP: Vascular surgical society of Great Britain and Ireland: angiogenesis and the atherosclerotic carotid plaque: association between symptomatology and plaque morphology. Br J Surg. 1999, 86: 707-708.

    Article  PubMed  Google Scholar 

  57. Virmani R, Kolodgie FD, Burke AP, Finn AV, Gold HK, Tulenko TN, Wrenn SP, Narula J: Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol. 2005, 25: 2054-2061. 10.1161/01.ATV.0000178991.71605.18.

    Article  CAS  PubMed  Google Scholar 

  58. Khatri JJ, Johnson C, Magid R, Lessner SM, Laude KM, Dikalov SI, Harrison DG, Sung HJ, Rong Y, Galis ZS: Vascular oxidant stress enhances progression and angiogenesis of experimental atheroma. Circulation. 2004, 109: 520-525. 10.1161/01.CIR.0000109698.70638.2B.

    Article  CAS  PubMed  Google Scholar 

  59. Vink A, Schoneveld AH, Lamers D, Houben AJ, van der Groep P, van Diest PJ, Pasterkamp G: HIF-1 alpha expression is associated with an atheromatous inflammatory plaque phenotype and upregulated in activated macrophages. Atherosclerosis. 2007, 195: e69-75. 10.1016/j.atherosclerosis.2007.05.026.

    Article  CAS  PubMed  Google Scholar 

  60. Luque A, Turu M, Juan-Babot O, Cardona P, Font A, Carvajal A, Slevin M, Iborra E, Rubio F, Badimon L, Krupinski J: Overexpression of hypoxia/inflammatory markers in atherosclerotic carotid plaques. Front Biosci. 2008, 13: 6483-6490.

    Article  CAS  PubMed  Google Scholar 

  61. Loots MA, Lamme EN, Mekkes JR, Bos JD, Middelkoop E: Cultured fibroblasts from chronic diabetic wounds on the lower extremity (non-insulin-dependent diabetes mellitus) show disturbed proliferation. Arch Dermatol Res. 1999, 291: 93-99. 10.1007/s004030050389.

    Article  CAS  PubMed  Google Scholar 

  62. Loots MA, Lamme EN, Zeegelaar J, Mekkes JR, Bos JD, Middelkoop E: Differences in cellular infiltrate and extracellular matrix of chronic diabetic and venous ulcers versus acute wounds. J Invest Dermatol. 1998, 111: 850-857. 10.1046/j.1523-1747.1998.00381.x.

    Article  CAS  PubMed  Google Scholar 

  63. Shyng YC, Devlin H, Sloan P: The effect of streptozotocin-induced experimental diabetes mellitus on calvarial defect healing and bone turnover in the rat. Int J Oral Maxillofac Surg. 2001, 30: 70-74. 10.1054/ijom.2000.0004.

    Article  CAS  PubMed  Google Scholar 

  64. Ferguson MW, Herrick SE, Spencer MJ, Shaw JE, Boulton AJ, Sloan P: The histology of diabetic foot ulcers. Diabet Med. 1996, Suppl 1: S30-33.

    Google Scholar 

  65. Kalluri R, Zeisberg M: Fibroblasts in cancer. Nat Rev Cancer. 2006, 6: 392-401. 10.1038/nrc1877.

    Article  CAS  PubMed  Google Scholar 

  66. Rhee S: Fibroblasts in three dimensional matrices: cell migration and matrix remodeling. Exp Mol Med. 2009, 41: 858-865. 10.3858/emm.2009.41.12.096.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  67. Yang H, Ganguly A, Cabral F: Inhibition of cell migration and cell division correlates with distinct effects of microtubule inhibiting drugs. J Biol Chem. 2010, 285: 32242-32250. 10.1074/jbc.M110.160820.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Loomans CJ, de Koning EJ, Staal FJ, Rookmaaker MB, Verseyden C, de Boer HC, Verhaar MC, Braam B, Rabelink TJ, van Zonneveld AJ: Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of type 1 diabetes. Diabetes. 2004, 53: 195-199.

    Article  CAS  PubMed  Google Scholar 

  69. Tepper OM, Galiano RD, Capla JM, Kalka C, Gagne PJ, Jacobowitz GR, Levine JP, Gurtner GC: Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation. 2002, 106: 2781-2786. 10.1161/01.CIR.0000039526.42991.93.

    Article  PubMed  Google Scholar 

  70. Fadini GP, Agostini C, Avogaro A: Endothelial progenitor cells and vascular biology in diabetes mellitus: current knowledge and future perspectives. Curr Diabetes Rev. 2005, 1: 41-58. 10.2174/1573399052952640.

    Article  CAS  PubMed  Google Scholar 

  71. Hoffmann J, Haendeler J, Aicher A, Rossig L, Vasa M, Zeiher AM, Dimmeler S: Aging enhances the sensitivity of endothelial cells toward apoptotic stimuli: important role of nitric oxide. Circ Res. 2001, 89: 709-715. 10.1161/hh2001.097796.

    Article  CAS  PubMed  Google Scholar 

  72. Keswani SG, Katz AB, Lim FY, Zoltick P, Radu A, Alaee D, Herlyn M, Crombleholme TM: Adenoviral mediated gene transfer of PDGF-B enhances wound healing in type I and type II diabetic wounds. Wound Repair Regen. 2004, 12: 497-504. 10.1111/j.1067-1927.2004.12501.x.

    Article  PubMed  Google Scholar 

  73. Loomans CJ, Dao HH, van Zonneveld AJ, Rabelink TJ: Is endothelial progenitor cell dysfunction involved in altered angiogenic processes in patients with hypertension?. Curr Hypertens Rep. 2004, 6: 51-54. 10.1007/s11906-004-0011-y.

    Article  PubMed  Google Scholar 

  74. Vasa M, Fichtlscherer S, Adler K, Aicher A, Martin H, Zeiher AM, Dimmeler S: Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation. 2001, 103: 2885-2890. 10.1161/hc2401.092816.

    Article  CAS  PubMed  Google Scholar 

  75. Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, Zeiher AM, Dimmeler S: Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res. 2001, 89: E1-7. 10.1161/hh1301.093953.

    Article  CAS  PubMed  Google Scholar 

  76. Ii M, Takenaka H, Asai J, Ibusuki K, Mizukami Y, Maruyama K, Yoon YS, Wecker A, Luedemann C, Eaton E, Silver M, Thorne T, Losordo DW: Endothelial progenitor thrombospondin-1 mediates diabetes-induced delay in reendothelialization following arterial injury. Circ Res. 2006, 98: 697-704. 10.1161/01.RES.0000209948.50943.ea.

    Article  CAS  PubMed  Google Scholar 

  77. Liu ZJ, Velazquez OC: Hyperoxia, endothelial progenitor cell mobilization, and diabetic wound healing. Antioxid Redox Signal. 2008, 10: 1869-1882. 10.1089/ars.2008.2121.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  78. Gallagher KA, Liu ZJ, Xiao M, Chen H, Goldstein LJ, Buerk DG, Nedeau A, Thom SR, Velazquez OC: Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1 alpha. J Clin Invest. 2007, 117: 1249-1259. 10.1172/JCI29710.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  79. Albiero M, Menegazzo L, Boscaro E, Agostini C, Avogaro A, Fadini GP: Defective recruitment, survival and proliferation of bone marrow-derived progenitor cells at sites of delayed diabetic wound healing in mice. Diabetologia. 2011, 54: 945-953. 10.1007/s00125-010-2007-2.

    Article  CAS  PubMed  Google Scholar 

  80. Barone BB, Yeh HC, Snyder CF, Peairs KS, Stein KB, Derr RL, Wolff AC, Brancati FL: Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis. JAMA. 2008, 300: 2754-2764. 10.1001/jama.2008.824.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Barone BB, Yeh HC, Snyder CF, Peairs KS, Stein KB, Derr RL, Wolff AC, Brancati FL: Postoperative mortality in cancer patients with preexisting diabetes: systematic review and meta-analysis. Diabetes Care. 2010, 33: 931-939. 10.2337/dc09-1721.

    Article  PubMed Central  PubMed  Google Scholar 

  82. van de Poll-Franse LV, Houterman S, Janssen-Heijnen ML, Dercksen MW, Coebergh JW, Haak HR: Less aggressive treatment and worse overall survival in cancer patients with diabetes: a large population based analysis. Int J Cancer. 2007, 120: 1986-1992. 10.1002/ijc.22532.

    Article  CAS  PubMed  Google Scholar 

  83. Eichholz A, Merchant S, Gaya AM: Anti-angiogenesis therapies: their potential in cancer management. Onco Targets Ther. 2010, 3: 69-82.

    PubMed Central  CAS  PubMed  Google Scholar 

  84. Novosyadlyy R, Lann DE, Vijayakumar A, Rowzee A, Lazzarino DA, Fierz Y, Carboni JM, Gottardis MM, Pennisi PA, Molinolo AA, Kurshan N, Mejia W, Santopietro S, Yakar S, Wood TL, LeRoith D: Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes. Cancer Res. 2010, 70: 741-751. 10.1158/0008-5472.CAN-09-2141.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  85. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ: Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003, 348: 1625-1638. 10.1056/NEJMoa021423.

    Article  PubMed  Google Scholar 

  86. Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R: Diabetes and cancer. Endocr Relat Cancer. 2009, 16: 1103-1123. 10.1677/ERC-09-0087.

    Article  CAS  PubMed  Google Scholar 

  87. Wu Y, Brodt P, Sun H, Mejia W, Novosyadlyy R, Nunez N, Chen X, Mendoza A, Hong SH, Khanna C, Yakar S: Insulin-like growth factor-I regulates the liver microenvironment in obese mice and promotes liver metastasis. Cancer Res. 2010, 70: 57-67. 10.1158/0008-5472.CAN-09-2472.

    Article  CAS  PubMed  Google Scholar 

  88. Erion DM, Shulman GI: Diacylglycerol-mediated insulin resistance. Nat Med. 2010, 16: 400-402. 10.1038/nm0410-400.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  89. Samuel VT, Petersen KF, Shulman GI: Lipid-induced insulin resistance: unravelling the mechanism. Lancet. 2010, 375: 2267-2277. 10.1016/S0140-6736(10)60408-4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  90. Rosse C, Linch M, Kermorgant S, Cameron AJ, Boeckeler K, Parker PJ: PKC and the control of localized signal dynamics. Nat Rev Mol Cell Biol. 2010, 11: 103-112. 10.1038/nrm2847.

    Article  CAS  PubMed  Google Scholar 

  91. Naldini A, Carraro F: Role of inflammatory mediators in angiogenesis. Curr Drug Targets Inflamm Allergy. 2005, 4: 3-8. 10.2174/1568010053622830.

    Article  CAS  PubMed  Google Scholar 

  92. Wellen KE, Hotamisligil GS: Inflammation, stress, and diabetes. J Clin Invest. 2005, 115: 1111-1119.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  93. Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, Osterreicher CH, Takahashi H, Karin M: Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010, 140: 197-208. 10.1016/j.cell.2009.12.052.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  94. Park HY, Kwon HM, Lim HJ, Hong BK, Lee JY, Park BE, Jang Y, Cho SY, Kim HS: Potential role of leptin in angiogenesis: leptin induces endothelial cell proliferation and expression of matrix metalloproteinases in vivo and in vitro. Exp Mol Med. 2001, 33: 95-102.

    Article  CAS  PubMed  Google Scholar 

  95. Ribeiro AM, Andrade S, Pinho F, Monteiro JD, Costa M, Lopes C, Aguas AP, Monteiro MP: Prostate cancer cell proliferation and angiogenesis in different obese mice models. Int J Exp Pathol. 2010, 91: 374-386. 10.1111/j.1365-2613.2010.00726.x.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  96. Gonzalez RR, Cherfils S, Escobar M, Yoo JH, Carino C, Styer AK, Sullivan BT, Sakamoto H, Olawaiye A, Serikawa T, Lynch MP, Rueda BR: Leptin signaling promotes the growth of mammary tumors and increases the expression of vascular endothelial growth factor (VEGF) and its receptor type two (VEGF-R2). J Biol Chem. 2006, 281: 26320-26328. 10.1074/jbc.M601991200.

    Article  CAS  PubMed  Google Scholar 

  97. Rene Gonzalez R, Watters A, Xu Y, Singh UP, Mann DR, Rueda BR, Penichet ML: Leptin-signaling inhibition results in efficient anti-tumor activity in estrogen receptor positive or negative breast cancer. Breast Cancer Res. 2009, 11: R36-10.1186/bcr2321.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  98. Sharma D, Saxena NK, Vertino PM, Anania FA: Leptin promotes the proliferative response and invasiveness in human endometrial cancer cells by activating multiple signal-transduction pathways. Endocr Relat Cancer. 2006, 13: 629-640. 10.1677/erc.1.01169.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  99. Bartucci M, Svensson S, Ricci-Vitiani L, Dattilo R, Biffoni M, Signore M, Ferla R, De Maria R, Surmacz E: Obesity hormone leptin induces growth and interferes with the cytotoxic effects of 5-fluorouracil in colorectal tumor stem cells. Endocr Relat Cancer. 2010, 17: 823-833. 10.1677/ERC-10-0083.

    Article  CAS  PubMed  Google Scholar 

  100. Baker L, Piddington R: Diabetic embryopathy: a selective review of recent trends. J Diabetes Complications. 1993, 7: 204-212. 10.1016/1056-8727(93)90046-2.

    Article  CAS  PubMed  Google Scholar 

  101. Cockroft DL, Coppola PT: Teratogenic effects of excess glucose on head-fold rat embryos in culture. Teratology. 1977, 16: 141-146. 10.1002/tera.1420160205.

    Article  CAS  PubMed  Google Scholar 

  102. Eriksson UJ, Borg LA, Forsberg H, Styrud J: Diabetic embryopathy. Studies with animal and in vitro models. Diabetes. 1991, Suppl 2: 94-98.

    Article  Google Scholar 

  103. Pinter E, Reece EA, Leranth CZ, Garcia-Segura M, Hobbins JC, Mahoney MJ, Naftolin F: Arachidonic acid prevents hyperglycemia-associated yolk sac damage and embryopathy. Am J Obstet Gynecol. 1986, 155: 691-702.

    Article  CAS  PubMed  Google Scholar 

  104. Pinter E, Reece EA, Leranth CZ, Sanyal MK, Hobbins JC, Mahoney MJ, Naftolin F: Yolk sac failure in embryopathy due to hyperglycemia: ultrastructural analysis of yolk sac differentiation associated with embryopathy in rat conceptuses under hyperglycemic conditions. Teratology. 1986, 33: 73-84. 10.1002/tera.1420330110.

    Article  CAS  PubMed  Google Scholar 

  105. Reece EA, Homko CJ, Wu YK: Multifactorial basis of the syndrome of diabetic embryopathy. Teratology. 1996, 54: 171-182. 10.1002/(SICI)1096-9926(199610)54:4<171::AID-TERA1>3.0.CO;2-4.

    Article  CAS  PubMed  Google Scholar 

  106. Reece EA, Homko CJ, Hagay Z: Prenatal diagnosis and prevention of diabetic embryopathy. Obstet Gynecol Clin North Am. 1996, 23: 11-28. 10.1016/S0889-8545(05)70242-4.

    Article  CAS  PubMed  Google Scholar 

  107. Ferencz C, Rubin JD, McCarter RJ, Clark EB: Maternal diabetes and cardiovascular malformations: predominance of double outlet right ventricle and truncus arteriosus. Teratology. 1990, 41: 319-326. 10.1002/tera.1420410309.

    Article  CAS  PubMed  Google Scholar 

  108. Pinter E, Mahooti S, Wang Y, Imhof BA, Madri JA: Hyperglycemia-induced vasculopathy in the murine vitelline vasculature: correlation with PECAM-1/CD31 tyrosine phosphorylation state. Am J Pathol. 1999, 154: 1367-1379. 10.1016/S0002-9440(10)65391-6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  109. Yang P, Reece EA: Role of HIF-1alpha in maternal hyperglycemia-induced embryonic vasculopathy. Am J Obstet Gynecol. 2011, 204: 332.

    PubMed Central  PubMed  Google Scholar 

  110. Kanasaki K, Kalluri R: The biology of preeclampsia. Kidney Int. 2009, 76: 831-837. 10.1038/ki.2009.284.

    Article  PubMed Central  PubMed  Google Scholar 

  111. Casey BM, Lucas MJ, McIntire DD, Leveno KJ: Pregnancy outcomes in women with gestational diabetes compared with the general obstetric population. Obstet Gynecol. 1997, 90: 869-873. 10.1016/S0029-7844(97)00542-5.

    Article  CAS  PubMed  Google Scholar 

  112. Yogev Y, Langer O: Recurrence of gestational diabetes: pregnancy outcome and birth weight diversity. J Matern Fetal Neonatal Med. 2004, 15: 56-60. 10.1080/14767050310001650734.

    Article  CAS  PubMed  Google Scholar 

  113. Yogev Y, Langer O, Brustman L, Rosenn B: Pre-eclampsia and gestational diabetes mellitus: does a correlation exist early in pregnancy?. J Matern Fetal Neonatal Med. 2004, 15: 39-43. 10.1080/14767050310001650707.

    Article  CAS  PubMed  Google Scholar 

  114. Innes KE, Wimsatt JH, McDuffie R: Relative glucose tolerance and subsequent development of hypertension in pregnancy. Obstet Gynecol. 2001, 97: 905-910. 10.1016/S0029-7844(01)01342-4.

    Article  CAS  PubMed  Google Scholar 

  115. Joffe GM, Esterlitz JR, Levine RJ, Clemens JD, Ewell MG, Sibai BM, Catalano PM: The relationship between abnormal glucose tolerance and hypertensive disorders of pregnancy in healthy nulliparous women. Calcium for Preeclampsia Prevention (CPEP) Study Group. Am J Obstet Gynecol. 1998, 179: 1032-1037. 10.1016/S0002-9378(98)70210-8.

    Article  CAS  PubMed  Google Scholar 

  116. Carpenter MW: Gestational diabetes, pregnancy hypertension, and late vascular disease. Diabetes Care. 2007, Suppl 2: S246-250.

    Article  CAS  Google Scholar 

  117. Yogev C, Hod , Coustan , Oats , McIntyre , Metzger , Lowe , Dyer , Dooley , Trimble , McCance , Hadden , Persson , Rogers , Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study Cooperative Research Group: Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study: preeclampsia. Am J Obstet Gynecol. 2010, 202: 255-257.

    PubMed  Google Scholar 

  118. Pinter E, Haigh J, Nagy A, Madri JA: Hyperglycemia-induced vasculopathy in the murine conceptus is mediated via reductions of VEGF-A expression and VEGF receptor activation. Am J Pathol. 2001, 158: 1199-1206. 10.1016/S0002-9440(10)64069-2.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  119. Kanasaki K, Palmsten K, Sugimoto H, Ahmad S, Hamano Y, Xie L, Parry S, Augustin HG, Gattone VH, Folkman J, Strauss JF, Kalluri R: Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia. Nature. 2008, 453: 1117-1121. 10.1038/nature06951.

    Article  CAS  PubMed  Google Scholar 

  120. Lee SB, Wong AP, Kanasaki K, Xu Y, Shenoy VK, McElrath TF, Whitesides GM, Kalluri R: Preeclampsia: 2-methoxyestradiol induces cytotrophoblast invasion and vascular development specifically under hypoxic conditions. Am J Pathol. 2010, 176: 710-720. 10.2353/ajpath.2010.090513.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  121. Shenoy V, Kanasaki K, Kalluri R: Pre-eclampsia: connecting angiogenic and metabolic pathways. Trends Endocrinol Metab. 2010, 21: 529-536. 10.1016/j.tem.2010.05.002.

    Article  CAS  PubMed  Google Scholar 

  122. Redman CW, Sargent IL: Preeclampsia and the systemic inflammatory response. Semin Nephrol. 2004, 24: 565-570.

    Article  PubMed  Google Scholar 

  123. Redman CW, Sargent IL: Latest advances in understanding preeclampsia. Science. 2005, 308: 1592-1594. 10.1126/science.1111726.

    Article  CAS  PubMed  Google Scholar 

  124. Sargent IL, Borzychowski AM, Redman CW: NK cells and human pregnancy–an inflammatory view. Trends Immunol. 2006, 27: 399-404. 10.1016/j.it.2006.06.009.

    Article  CAS  PubMed  Google Scholar 

  125. Sargent IL, Borzychowski AM, Redman CW: NK cells and pre-eclampsia. J Reprod Immunol. 2007, 76: 40-44. 10.1016/j.jri.2007.03.009.

    Article  CAS  PubMed  Google Scholar 

  126. Moisseiev E, Goldstein M, Loewenstein A, Moisseiev J: Macular hole following intravitreal bevacizumab injection in choroidal neovascularization caused by age-related macular degeneration. Case Report Ophthalmol. 2010, 1: 36-41. 10.1159/000319827.

    Article  Google Scholar 

  127. Wong LJ, Desai RU, Jain A, Feliciano D, Moshfeghi DM, Sanislo SR, Blumenkranz MS: Surveillance for potential adverse events associated with the use of intravitreal bevacizumab for retinal and choroidal vascular disease. Retina. 2008, 28: 1151-1158. 10.1097/IAE.0b013e31817e100f.

    Article  PubMed  Google Scholar 

  128. Georgopoulos M, Polak K, Prager F, Prunte C, Schmidt-Erfurth U: Characteristics of severe intraocular inflammation following intravitreal injection of bevacizumab (Avastin). Br J Ophthalmol. 2009, 93: 457-462. 10.1136/bjo.2008.138479.

    Article  CAS  PubMed  Google Scholar 

  129. Querques G, Souied EH, Soubrane G: Macular hole following intravitreal ranibizumab injection for choroidal neovascular membrane caused by age-related macular degeneration. Acta Ophthalmol. 2009, 87: 235-237.

    Article  PubMed  Google Scholar 

  130. Chung EJ, Koh HJ: Retinal detachment with macular hole following combined photodynamic therapy and intravitreal bevacizumab injection. Korean J Ophthalmol. 2007, 21: 185-187. 10.3341/kjo.2007.21.3.185.

    Article  PubMed Central  PubMed  Google Scholar 

  131. Mitamura Y, Ogata K, Oshitari T, Asaumi N, Yamamoto S: Retinal detachment with macular hole following intravitreal bevacizumab in patient with severe proliferative diabetic retinopathy. Br J Ophthalmol. 2008, 92: 717-718. 10.1136/bjo.2008.139378.

    Article  PubMed  Google Scholar 

  132. Maeshima Y, Makino H: Angiogenesis and chronic kidney disease. Fibrogenesis Tissue Repair. 2010, 3: 13-10.1186/1755-1536-3-13.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

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Acknowledgments

KK, DK, and MK are supported by grants from the Japan Society for the Promotion of Science and several foundation grants. LX was supported by the foreign scholar grants from Kanazawa Medical University.

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Correspondence to Keizo Kanasaki.

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LX contributed to writing the manuscript and made figures. MK was involved in the discussion. DK made intellectual contributions. KK conceived the project, provided intellectual contribution, and contributed to the manuscript writing and editing. All authors read and approved the final manuscript.

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Xu, L., Kanasaki, K., Kitada, M. et al. Diabetic angiopathy and angiogenic defects. Fibrogenesis Tissue Repair 5, 13 (2012). https://doi.org/10.1186/1755-1536-5-13

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