Deletion of Lymphangiogenic and Angiogenic Growth Factor VEGF (Vascular Endothelial Growth Factor)-D Leads to Severe Hyperlipidemia and Delayed Clearance of CR (Chylomicron Remnants)

Objective— Dyslipidemia is one of the key factors behind coronary heart disease. Blood and lymphatic vessels play pivotal roles in both lipoprotein metabolism and development of atherosclerotic plaques. Recent studies have linked members of VEGF (vascular endothelial growth factor) family to lipid metabolism, but the function of VEGF-D has remained unexplored. Here, we investigated how the deletion of VEGF-D affects lipid and lipoprotein metabolism in atherogenic LDLR−/− (low-density lipoprotein receptor) ApoB100/100 mice. Approach and Results— Deletion of VEGF-D (Vegfd−/−LDLR−/−ApoB100/100) led to markedly elevated plasma cholesterol and triglyceride levels without an increase in atherogenesis. Size distribution and hepatic lipid uptake studies confirmed a delayed clearance of large CR (chylomicron remnant) particles that cannot easily penetrate through the vascular endothelium. Mechanistically, the inhibition of VEGF-D signaling significantly decreased the hepatic expression of SDC1 (syndecan 1), which ...