Arterial Hypoxia in Hyperglycemic Accelerated Atherosclerosis

Abstract

Individuals with diabetes mellitus (DM) have a 2 to 4-fold increased risk of cardiovascular diseases (CVD) compared to those without DM. A contributing factor to the development of CVD is atherosclerosis, a chronic inflammatory disease causing plaque build-up in medium to larger arteries. Increasing evidence suggests that hypoxia within the arterial wall is known to promote atherosclerosis, however the underlying mechanisms remain unclear. Our lab has previously shown that hyperglycemic APOE-deficient mice have impaired angiogenesis of the aortic vasa vasorum, increased arterial hypoxia, elevated vascular inflammation and accelerated atherosclerosis development at 15 weeks of age compared to normoglycemic APOE-deficient controls. The objective of this study is to elucidate the mechanisms associated with these differences, specifically the reductions in vasa vasorum. The effects of hyperglycemia and specific interventions to modulate endoplasmic reticulum stress (4-phenylbutyric acid (4PBA)), oxidative stress (n-acetyl-cysteine (NAC)) and advanced glycation end products (pyridoxamine (PX)) are examined in vivo and in vitro. Results demonstrate that human cardiac microvascular endothelial cells (HMVEC-Cs) have reduced angiogenesis in high glucose compared to normal glucose conditions in both hypoxic and normoxic environments. This may be associated with reduced expression of vascular endothelial growth factor A (VEGF-A). Treatment with PX or NAC in hypoxic, high glucose conditions increased the angiogenesis and expression of VEGF-A in HMVEC-Cs. Pilot studies suggest that PX, NAC or 4PBA supplementation are well tolerated in drinking water using STZ mouse models. Future studies should assess the direct effects of each of the chemical interventions on vasa vasorum angiogenesis, arterial hypoxia and atherosclerosis. These results suggest that oxidative stress and advanced glycation end products play a more significant role in reducing microvessel angiogenesis in vitro. Understanding of the non-canonical pathways of atherosclerosis progression in the presence of DM will facilitate the development of novel and more specific treatments for this ongoing epidemic.