Hyperglycemia-Induced Vasculopathy in the Murine Conceptus Is Mediated via Reductions of VEGF-A Expression and VEGF Receptor Activation

Abstract

Major congenital malformations, including those affecting the cardiovascular system, remain the leading cause of mortality and morbidity in infants of diabetic mothers. Interestingly, targeted mutations of several genes (including VEGF and VEGF receptors) and many teratogenic agents (including excess D-glucose) that give rise to embryonic lethal phenotypes during organogenesis are associated with a failure in the formation and/or maintenance of a functional vitelline circulation. Given the similarities in the pathology of the abnormal vitelline circulation in many of these conditions, we hypothesized that the hyperglycemic insult present in diabetes could cause the resultant abnormalities in the vitelline circulation by affecting VEGF/VEGF receptor signaling pathway(s). In this study we report that hyperglycemic insult results in reduced levels of VEGF-A in the conceptus, which in turn, leads to abnormal VEGF receptor signaling, ultimately resulting in embryonic (vitelline) vasculopathy. These findings and our observation that addition of exogenous rVEGF-A(165) within a defined concentration range blunts the hyperglycemia-induced vasculopathy in the conceptus support the concept that VEGF levels can be modulated by glucose levels. In addition, these findings may ultimately lead to novel therapeutic approaches for the treatment of selected congenital cardiovascular abnormalities associated with diabetes.

Hyperglycemia-Induced Defects in Angiogenesis in the Chicken Chorioallantoic Membrane Model

“…Although the effect of hyperglycemia on angiogenesis is often presented as a stimulatory one, on the basis of what is observed in the late phase of diabetic retinopathy, defective angiogenesis has been observed in different models such as wound healing (20,21), embryonic growth (7,22), and transplantation of avascular islets of Langerhans (23).…”

“…impaired angiogenesis (7,22). In the model we used, a short-term, modest hyperglycemia without hypoinsulinemia was found to decrease embryonic angiogenesis in vivo.…”

“…The expression level of VEGF, the major vascular growth factor, has been found to be decreased by hyperglycemia in models where impaired angiogenesis was observed (7,20,21,24,25) and in fibroblasts isolated from diabetic embryos (26). The expression level of VEGF was found to be unaltered by hyperglycemia in other models (27,28) and increased at sites of aberrant angiogenesis in diabetic patients, particularly in the retina of diabetic patients with proliferative diabetic retinopathy (29).…”

“…In a murine model of short-term in vitro culture of embryos, it has been shown that hyperglycemia affects VEGF/VEGF receptor signaling pathways, causing arrest of vascular development at the primary capillary plexus stage in the yolk sac (7).…”

VEGF Expression in Hypoxia and Hyperglycemia

“…In the remnant kidney model, Kang et al (10) observed a strong correlation between the number of peritubular capillaries and tubular VEGF expression. Changes in VEGF production have been also studied under hypoxic and diabetic conditions, yielding some controversial findings (11,12).…”