Heparanase, Endothelial Dysfunction, and Cardiovascular Risk: The Emerging Role of Vitamin D.

Endothelial dysfunction is a central pathophysiological mechanism in the development of cardiovascular disease (CVD), the leading global cause of morbidity and mortality. Vascular homeostasis critically depends on the endothelial glycocalyx, which regulates vascular permeability, mechanotransduction, and anti-inflammatory signaling. Heparanase, the only known mammalian endoglycosidase capable of cleaving heparan sulfate, plays a pivotal role in glycocalyx degradation, a process exacerbated by oxidative stress, hyperglycemia, and hypertension. Excessive heparanase activity has been implicated in several cardiovascular pathologies, including heart failure, ischemia-reperfusion injury, and atherosclerosis, yet effective therapeutic strategies remain limited. Emerging evidence suggests that vitamin D may preserve endothelial integrity by maintaining the structure of the glycocalyx and suppressing heparanase expression, as demonstrated in podocytes. By attenuating heparanase-mediated degradation of the glycocalyx in the vasculature and heart, vitamin D could exert protective effects against endothelial dysfunction and thereby mitigate cardiovascular risk.