Flow patterns regulate hyperglycemia-induced subendothelial matrix remodeling during early atherogenesis

Abstract

Objective Altered subendothelial matrix composition regulates endothelial dysfunction and early atherosclerotic plaque formation. Hyperglycemia promotes endothelial matrix remodeling associated with multiple microvascular complications of diabetes, but a role for altered matrix composition in diabetic atherogenesis has not been described. Therefore, we sought to characterize the alterations in matrix composition during diabetic atherogenesis using both in vitro and in vivo model systems. Methods and Results Streptozotocin-induced diabetes in atherosclerosis-prone ApoE knockout mice promoted transitional matrix expression (fibronectin, thrombospondin-1) and deposition in intima of the aortic arch as determined by qRT-PCR array and immunohistochemistry. Early plaque formation occurs at discrete vascular sites exposed to disturbed blood flow patterns, whereas regions exposed to laminar flow are protected. Consistent with this pattern, hyperglycemia-induced transitional matrix deposition was restricted to regions of disturbed blood flow. Laminar flow significantly blunted high glucose-induced fibronectin expression (mRNA and protein) and fibronectin fibrillogenesis in endothelial cell culture models, whereas high glucose-induced fibronectin deposition was similar between disturbed flow and static conditions. Conclusions Taken together, these data demonstrate that flow patterns and hyperglycemia coordinately regulate subendothelial fibronectin deposition during early atherogenesis.

Lack of Fibronectin Extra Domain A Alternative Splicing Exacerbates Endothelial Dysfunction in Diabetes

“…Total fibronectin levels were comparable between aortas within both control and diabetic genotypes, with STZ treated groups showing a trend for increased protein deposition, in agreement with reports in humans and in rodent diabetic models2829 (Fig. 2a and d).…”

Endothelial fluid shear stress sensing in vascular health and disease

“…The importance of fibronectin in atherosclerosis is supported by animal studies demonstrating that genetic manipulations to reduce fibronectin in the vessel wall reduce plaque burden (70)(71)(72). Interestingly, diabetes, which is a potent risk factor for atherosclerosis, further increases fibronectin deposition in atherosclerosis-prone regions of arteries (73). Atherosclerosis may thus be seen as a form of flow-dependent remodeling that never resolves.…”

Haemodynamics Regulate Fibronectin Assembly via PECAM

“…Similarly, mice treated with a FN polymerization inhibitor are also characterized by reduced IMT and vascular remodeling2. Although endothelial responses to shear stress are known to regulate expression and deposition of ECM components11353637, virtually nothing is known about the role of shear stress in the regulation of FN assembly. We hypothesized that PECAM, a known endothelial mechanosensor is important for regulation of the organization of the subendothelial ECM, especially in response to shear stress.…”

“…Other studies have focused on the role of haemodynamics in the regulation of expression of ECM components. Atheroprone areas of the vasculature exhibit increased deposition of FN and ECs exposed to disturbed flow exhibit increased FN expression1135363738. Not surprisingly, the role of FN in inflammation and atherosclerosis is rather complex: while FN promotes increased plaque area, it has also been shown to promote formation of the protective fibrous cap, which in humans prevents plaque rupture39.…”