| Autor: |
Oliveira SDS; From the Department of Anesthesiology (S.D.S.O., M.C., R.D.M.), University of Illinois at Chicago., Chen J; Department of Medicine (J.C., M.M., R.F.M., M.G.B.), University of Illinois at Chicago.; Research Resources Center Cardiovascular Research Core (J.C., M.C.), University of Illinois at Chicago., Castellon M; From the Department of Anesthesiology (S.D.S.O., M.C., R.D.M.), University of Illinois at Chicago.; Research Resources Center Cardiovascular Research Core (J.C., M.C.), University of Illinois at Chicago., Mao M; Department of Medicine (J.C., M.M., R.F.M., M.G.B.), University of Illinois at Chicago., Raj JU; Department of Pediatrics (J.U.R.), University of Illinois at Chicago., Comhair S; Lerner Research Institute (S.C., S.E.), Cleveland Clinic Foundation, OH., Erzurum S; Lerner Research Institute (S.C., S.E.), Cleveland Clinic Foundation, OH., Silva CLM; Institute of Biomedical Science, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil (C.L.M.S.)., Machado RF; Department of Medicine (J.C., M.M., R.F.M., M.G.B.), University of Illinois at Chicago., Bonini MG; Department of Medicine (J.C., M.M., R.F.M., M.G.B.), University of Illinois at Chicago., Minshall RD; From the Department of Anesthesiology (S.D.S.O., M.C., R.D.M.), University of Illinois at Chicago.; Department of Pharmacology (R.D.M.), University of Illinois at Chicago. |
| Abstrakt: |
Objective- To determine whether pulmonary arterial hypertension is associated with endothelial cell (EC)-Cav-1 (caveolin-1) depletion, EC-derived extracellular vesicle cross talk with macrophages, and proliferation of Cav-1 depleted ECs via TGF-β (transforming growth factor-β) signaling. Approach and Results- Pulmonary vascular disease was induced in Sprague-Dawley rats by exposure to a single injection of VEGFRII (vascular endothelial growth factor receptor II) antagonist SU5416 (Su) followed by hypoxia (Hx) plus normoxia (4 weeks each-HxSu model) and in WT (wild type; Tie2.Cre - ; Cav1 lox/lox ) and EC- Cav1 -/- (Tie2.Cre + ; Cav1 fl/fl ) mice (Hx: 4 weeks). We observed reduced lung Cav-1 expression in the HxSu rat model in association with increased Cav-1+ extracellular vesicle shedding into the circulation. Whereas WT mice exposed to hypoxia exhibited increased right ventricular systolic pressure and pulmonary microvascular thickening compared with the group maintained in normoxia, the remodeling was further increased in EC- Cav1 -/- mice indicating EC Cav-1 expression protects against hypoxia-induced pulmonary hypertension. Depletion of EC Cav-1 was associated with reduced BMPRII (bone morphogenetic protein receptor II) expression, increased macrophage-dependent TGF-β production, and activation of pSMAD2/3 signaling in the lung. In vitro, in the absence of Cav-1, eNOS (endothelial NO synthase) dysfunction was implicated in the mechanism of EC phenotype switching. Finally, reduced expression of EC Cav-1 in lung histological sections from human pulmonary arterial hypertension donors was associated with increased plasma concentration of Cav-1, extracellular vesicles, and TGF-β, indicating Cav-1 may be a plasma biomarker of vascular injury and key determinant of TGF-β-induced pulmonary vascular remodeling. Conclusions- EC Cav-1 depletion occurs, in part, via Cav-1+ extracellular vesicle shedding into the circulation, which contributes to increased TGF-β signaling, EC proliferation, vascular remodeling, and pulmonary arterial hypertension. |
