Abstract 10: Endothelial FGF Protects Against Pulmonary Hypertension

Abstract

Pulmonary hypertension (PH) is a debilitating disease where 1 in 4 patients will die within five years of diagnosis. Pathologic changes of endothelial cell function, together with smooth muscle and adventitial hyperplasia increase pulmonary vascular resistance. Consequent elevation in right ventricular pressure ultimately causes right heart failure. Expression of Fibroblast Growth Factor Receptors (FGFRs), FGFR1 and FGFR2, are elevated in lung samples from PH patients; however, the impact of these receptors on endothelial cell function, and endothelial to smooth muscle interaction is poorly understood. We hypothesize that activation of endothelial FGFR1 and FGFR2 promotes endothelial cell survival, elaborating signals that protect against pulmonary hypertension via inhibition of smooth muscle cell recruitment. We used the Tie2-Cre transgene to conditionally inactivate Fgfr1 and Fgfr2 in endothelial cells. Experimental mice with genotype Tie2-Cre; Fgfr1 f/f ; Fgfr2 f/f (DCKO) and control Fgfr1 f/f ; Fgfr2 f/f (DFF) were challenged with 10% hypoxia for 2 weeks. At the end, right ventricular pressure (RVp) was measured by cardiac catheterization. Compared to mice in normoxia, control littermates in hypoxia demonstrated significant increases in RVp, and RV to left ventricle + septum (LV+S) weight ratio, consistent with development of PH. DCKO mice demonstrate further elevation in RVp and an increase in the RV to LV+S weight ratio, demonstrating worsening PH. We also observed formation of plexiform lesions in DCKO mice, suggestive of a severe pathology. We found a previously unreported involvement of FGF10 in pulmonary hypertension. FGF10 expression was decreased in hypoxia-challenged DCKO mice as compared to both DCKO littermates on room air, and to hypoxia challenged DFF control mice. Our data suggests that endothelial FGFR1 and FGFR2 activation may protect against pulmonary hypertension. Further studies are underway to elucidate the role of FGF10 and its mechanism in the pathology. We will also further identify associated FGF ligands, associated signaling mechanisms, and endothelial to smooth muscle interactions.