Endothelial CD36 is a key regulator of high-fat diet-induced endothelium stiffening and barrier disruption

The continued adoption of a Western-style high fat diet (WD) has a pervasive detrimental effect on human physiology, from increasing body adiposity to inflammation. WD is associated with an increase in plasma lipids, which are uptaken by endothelial cells (ECs) through scavenger receptors such as CD36. We have shown previously that CD36, a receptor for long-chain fatty acids and oxidized low-density lipoproteins, is required for lipid-induced activation of RhoA signaling and subsequent EC stiffening, by demonstrating that lipid-induced EC stiffening was prevented by downregulation of CD36 in vitro and ex vivo. To investigate the role of endothelial CD36, we generated a conditional endothelial-specific VE-cadherin-driven CD36 knockdown mouse model. Within 6-8 weeks, WD-fed wild-type (WT) mice exhibited a significant increase in the stiffening of the aortic EC layer, assessed through atomic force microscopy that measured Young’s modulus values across tissues. We discovered that an endothelial-specific knockdown of CD36 (EC-CD36KD) prevents WD-induced stiffening of the aortic EC layer. The rescue effect of EC-CD36KD on endothelial stiffness was independent of the blood cholesterol. In a sex comparison, we discovered that although both sexes have similar EC expression levels of CD36, only male mice developed a significant stiffening of the aortic EC layer while females did not. Following WD, we assessed barrier disruption through confocal microscopy to track the leakage of Evans blue dye across the aorta. While WT mice develop a significant barrier disruption, EC-CD36KD mice do not. Furthermore, we discovered that endothelial stiffening with age that we observed in 9 months old mice kept on normal chow, is also prevented in EC-CD36KD mice. Downregulation of endothelial CD36 also generates a protective trend against a prolonged 25 weeks of WD-induced endothelial stiffening. Finally, inducing CD36 knockdown at 9 months of age (after the stiffening has already developed) show a trend in partial reversal of ageing-associated EC stiffening, demonstrating that endothelial CD36 is a key regulator of vascular mechanical properties. We acknowledge financial support from NIH (IL), trainee grant funds from NIH and university support (VA). Results here do not represent the official views of these institutions This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.