Abstract 18804: Chronic Pressure Overload Impairs Cardiac Microvascular Endothelial Cell Metabolism and Angiogenic Potential in Aortic Stenosis Patients

Introduction: Chronic myocardial pressure overload leads to interstitial fibrosis and capillary rarefaction. We previously showed that transverse aortic constriction upregulates Transforming Growth Factor s (TGFs)-dependent fibrosis-related genes, including Cartilage Intermediate Layer Protein (CILP), in murine cardiac microvascular endothelial cells (MiVEC). Hypothesis: In aortic stenosis patients (AS), chronic pressure overload induces a phenotypic switch in cardiac MiVEC that impairs EC function and metabolism. Methods: We culture-expanded CD31+ MiVEC after MACS isolation from right atrium (RA, low pressure) and left ventricular outflow tract (LVOT, pressure overload) surgical biopsies of AS and exposed them to TGFs and the TGFs-1 receptor inhibitor, SD208 for 48h. At p4, MiVEC angiogenic potential was determined using 2D tube formation and 3D spheroid sprouting. Glycolytic and oxidative metabolic fluxes were assessed using 3 H-5-Glucose and 3 H-9,10-palmitic acid. Results: In AS, CILP expression in LVOT positively correlated with LA dilation and pulmonary artery pressure (n=19, Pearson, P 300-fold in the presence of TGF-s (p=0.01) via activation of the SD208-inhibitable TGFs-1 receptor. LVOT MiVEC showed less sprouts/spheroid (12.84±2.01 vs 23.17±1.38 in RA MiVEC, P vs 30.55±3.57/cm 2 , P=0.03), less nodes (188.07±53.15 vs 273.14±62.76/cm 2 , P=0.03) and reduced total network length (7.95±1.34 vs 10.39±1.21 mm/mm 2 , P=0.02) compared to RA (n=6). Glycolytic flux was comparable (P=0.38), but palmitic acid flux was higher in LVOT-derived MiVEC (7.46±2.3 vs 3.54±1.10 nmol/h/mg protein in RA MiVEC, P Conclusions: Chronic pressure overload induces a molecular and metabolic switch in human cardiac MiVEC, characterized by TGFs-dependent CILP-upregulation, loss of angiogenic potential in vitro and increased fatty acid oxidation. These data, for the first time, identify human cardiac MiVEC as a critical target to reverse fibrosis and capillary rarefaction in pressure overloaded hearts.