Hyaluronan deficiency disrupts endothelial glycocalyx integrity and contributes to age-related arterial dysfunction.

Aging is accompanied by arterial dysfunction, defined by impaired endothelial function and increased large artery stiffness, yet the contribution of the endothelial glycocalyx (eGC) and its constituent, hyaluronan (HA), to this process remains incompletely understood. We tested the hypothesis that decreasing endothelial HA synthesis via a reduction in endothelial-specific HA synthase 2 (HAS2) compromises eGC integrity and contributes to arterial dysfunction with advancing age. Both endothelial-specific HAS2 reduction and aging impair eGC integrity, evidenced by impaired barrier function and reduced eGC thickness in vivo, and aging led to a reduction in circulating HA and an increase in syndecan-1. Similar to aging, reduced endothelial HA selectively attenuated flow-induced endothelium-dependent dilation (EDD) and eNOS activation, whereas agonist-induced EDD was preserved in young arteries despite the concomitant eGC dysfunction. In parallel, reduced HAS2 expression and advancing age were each associated with increased aortic stiffness and adverse arterial remodeling, including excessive collagen deposition and reduced elastin. Collectively, these findings identify endothelial HA as a key determinant of eGC integrity and endothelial function, linking impaired HA availability to the development of arterial dysfunction with advancing age.