Endothelial Cell Caveolin‐1 Depletion Modulates TGF and Notch Signaling Associated with Pulmonary Arterial Hypertension

Abstract

Reduced expression of caveolin‐1 (Cav1) in endothelial cells (ECs) is associated with pulmonary vascular remodeling. Pulmonary vascular pathology in global Cav1−/− mice is prevented when eNOS is also deleted. Thus, we hypothesized that eNOS‐derived oxidants in absence of Cav‐1 result in dysfunctional ECs and pathological vascular remodeling. Hypoxia exposure following VEGFRII inhibition in Sprague‐Dawley rats produced a significant reduction in pulmonary Cav‐1 expression. Moreover, C57BL6 WT (Tie2.Cre−;Cav1lox/lox) mice exposed for 1 month to hypoxia exhibited an increase in the right ventricular systolic pressure (RVSP) from 25.33 to 31.68 ± 1.75 mmHg which was even higher in EC‐Cav1−/− (Tie2.Cre+;Cav1lox/lox) mice (27.95 to *38.48 ± 1.76 mmHg) when compared to normoxia. The increase in pulmonary arterial pressure induced by hypoxia was associated mild cardiac hypertrophy, increased plasma TGF‐β levels, and increased microvascular area/thickness indicative of vascular remodeling. Interestingly, under normoxic conditions, we observed reduced VEGF level in the lungs of EC‐Cav1−/− mice (8998 ± 1062 and 4927 ± 505.4 pg/mL, n=3–7 mice) suggesting Cav‐1 expression may be required to maintain normal VEGF signaling. Since VEGFRII inhibition may promote EC injury, we hypothesized that in the absence of endothelial Cav‐1, a defect in VEGF‐dependent vascular repair after injury may be the mechanism underlying pathological vascular remodeling. Then, mouse lung ECs (MLECs) isolated from WT, Cav1−/−, and Cav1−/−;eNOS−/− mice were used to assess gene and protein expression, and to quantify indices of angiogenesis. We have observed a defect in tube formation in Cav1−/− MLECs which was abo‐lished with genetic ablation of eNOS−/−. Moreover, in support of these findings, we observed increased Notch‐2 and ‐3 gene expression, and reduced Notch‐1 cleavage in Cav1−/− but not Cav1−/−;eNOS−/− MLECs. Finally, our data suggest the absence of endothelial Cav‐1 may promote pathological vascular remodeling by modulating TGF‐β and Notch signaling.Support or Funding InformationCNPq Fellowship‐CsF/Brazil; HL125356; DOD W911NF‐15‐R‐002.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.