Type I interferon activation and endothelial dysfunction in caveolin-1 insufficiency-associated pulmonary arterial hypertension

Significance Caveolin-1 (CAV1) loss-of-function mutations are a hereditary cause of pulmonary arterial hypertension (PAH), but wild-type CAV1 is also decreased in the vascular lesions of idiopathic and disease-associated PAH. Using human pulmonary artery endothelium, lung tissue, and serum from Cav1 −/− mice, as well as fibroblasts and serum from patients with CAV1 mutations, CAV1 deficiency produced a dysfunctional, PAH-like endothelial phenotype driven by an interferon-biased inflammatory response with constitutive STAT and AKT activation. Inhibiting JAK/STAT and PI3K/AKT reversed the aberrant endothelial phenotype of CAV1 loss and may similarly ameliorate pathologic vascular remodeling in PAH. Exogenous interferon alone reduced CAV1 expression and activated these same signaling pathways, suggesting that CAV1 insufficiency may contribute to the development of autoimmune and autoinflammatory disease-associated PAH.