Inflammation-induced caveolin-1 and BMPRII depletion promotes endothelial dysfunction and TGF-β-driven pulmonary vascular remodeling

Abstract

Endothelial cell (EC) activation and vascular injury are hallmark features of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Caveolin-1 (Cav-1) is highly expressed in pulmonary microvascular ECs and plays a key role in maintaining vascular homeostasis. The aim of this study was to determine if the lung inflammatory response to lipopolysaccharide (LPS) promotes priming of ECs via Cav-1 depletion and if this contributes to the onset of pulmonary vascular remodeling. To test the hypothesis that depletion of Cav-1 primes ECs to respond to profibrotic signals, C57BL6 wild-type (WT) mice ( ) were exposed to nebulized LPS (10 mg; 1 h daily for 4 days) and compared with EC-specific ( ). After 96 h of LPS exposure, total lung Cav-1 and bone morphogenetic protein receptor type II (BMPRII) expression were reduced in WT mice. Moreover, plasma albumin leakage, infiltration of immune cells, and levels of IL-6/IL-6R and transforming growth factor-β (TGF-β) were elevated in both LPS-treated WT and mice. Finally, mice exhibited a modest increase in microvascular thickness basally and even more so on exposure to LPS (96 h). mice and LPS-treated WT mice exhibited reduced BMPRII expression and endothelial nitric oxide synthase uncoupling, which along with increased TGF-β promoted TGFβRI-dependent SMAD-2/3 phosphorylation. Finally, human lung sections from patients with ARDS displayed reduced EC Cav-1 expression, elevated TGF-β levels, and severe pulmonary vascular remodeling. Thus EC Cav-1 depletion, oxidative stress-mediated reduction in BMPRII expression, and enhanced TGF-β-driven SMAD-2/3 signaling promote pulmonary vascular remodeling in inflamed lungs.

Reciprocal regulation of eNOS and caveolin-1 functions in endothelial cells

“…, 2013 ), nitrate tolerance ( Mao et al. , 2014 ), and inflammation-induced pulmonary vascular remodeling ( Oliveira et al. , 2017 ).…”

“…Depletion of Cav-1 and resultant reduction in number of caveolae have recently been linked to a wide range of human disease states, including cardiovascular and pulmonary disease ( Bakhshi et al. , 2013 ; Parton and del Pozo, 2013 ; Oliveira et al. , 2017 ).…”

Neuroretinal-derived caveolin-1 promotes endotoxin-induced inflammation in the murine retina

“…Animals carrying Chx10-promoter-driven Cre recombinase (stock#: 005105, The Jackson Laboratory, Bar Harbor, ME) were bred with animals carrying the Cav1 gene flanked by Lox P sites located upstream and downstream of exon 2 (25). Endothelial-specific Cav1 knock-out mice (Tie2-Cre; Cav1 flox/flox ) were generated similarly, using endothelial cell-specific recombination (B6.Cg-Tg (Tek-cre) 1Ywa/J; stock#: 008863, The Jackson Laboratory, Bar Harbor, ME) (26). Cre-negative littermates were used as controls.…”

Caveolin as a Novel Potential Therapeutic Target in Cardiac and Vascular Diseases: A Mini Review

“…Endothelial dysfunction, which is characterized by inflammation and oxidative stress, is the first step of pulmonary vascular wall damage. Endothelial injury caused by proinflammatory mediators leads to caveolin-1 depletion and eNOS uncoupling, consequently priming endothelial cells into a proinflammatory phenotype linked to oxidative stress-mediated BMPRII reduction; this is accompanied by elevated TGF-β, which promotes pulmonary vascular remodeling [58]. As a result, pulmonary hypertension occurs due to hyperactive eNOS and subsequent tyrosine nitration-dependent impaired PKG activity [59].…”