The Role of Endothelial CXCR4 in Cardiovascular Diseases

The CXCR4/CXCL12 signaling pathways are crucial for embryogenesis, cardiovascular development and regeneration. Endothelial cells are essential for maintaining vascular homeostasis, but the role of endothelial CXCR4 is not fully understood. In this study, we investigate the role of endothelial CXCR4 in vascular homeostasis and cardiovascular diseases. Global deletion of CXCR4 is embryonic lethal with defects in vascular development, hematopoiesis, and cardiogenesis. First, we generated non-inducible endothelial cells (EC)-specific Cxcr4 knockouts, Cxcr4DEC (Cxcr4f/f, tie-2 cre), which are viable. To exclude its effect on embryonic development, we generated inducible EC-specific Cxcr4 knockouts, Cxcr4iDEC (Cxcr4f/f, Cadh5-Cre-ER). We compared the phenotype of both mice to investigate the role of endothelial CXCR4. In the previous study, we found aortic stenosis in Cxcr4DEC mice. However, the Cxcr4iDEC mice did not phenotype the Cxcr4DEC mice. Therefore, we focus on the non-inducible Cxcr4 EC knockouts. In this study, we will determine the role of endothelial CXCR4 on aortic aneurysms. We use a mouse model of aneurysm induced by β-Aminopropionitrile (BAPN), a specific, irreversible inhibitor of lysyl oxidase (LOX). Young Cxcr4DEC mice (4 weeks) were treated with 3% BAPN water for 30 days. We measured cardiac function using echocardiography, and we imaged and quantified heart size, aortic diameters, and fibrosis. Moreover, we studied the role of CXCR4 in vascular function and measured vasodilation in Cxcr4DEC mice with myography (DMT). We are exploring molecular mechanisms with gene expression and immunostaining. Our preliminary data showed that CXCR4 deletion in endothelial cells impaired endothelial-dependent vasodilation and cardiovascular function, accompanied by thickening and false lumens in the ascending and descending aorta, increased aortic rupture, and mortality. These results indicate that endothelial CXCR4 deficiency caused severe aortic pathologies, compromising the aorta's contractile abilities which suggests the essential role of CXCR4/CXCL12 signaling for cardiovascular homeostasis. 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.