Extensive Endothelial Damage in an Inflammatory Model of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease associated with right heart failure and premature death. Diagnosis of PAH is often made late and available therapy fails to reverse the disease process. To test the hypothesis that the poor response to therapy in PAH is due to the involvement of multiple signaling pathways, we investigated time‐dependent changes in the expression of caveolin‐1, PY‐STAT3, Bcl‐xL, and the molecules involved in NO signaling pathway (eNOS, HSP90, Akt) in rats at 48 hr, 1, 2, and 3 wks post‐monocrotaline (MCT). Progressive PAH, right ventricular hypertrophy and pulmonary vascular remodeling were observed at 2 and 3 wks post‐MCT. Progressive loss of endothelial caveolin‐1 coupled with activation of PY‐STAT3 and upregulation of Bcl‐xL preceded the onset of PAH. There was an early and progressive loss of Tie2 which colocalizes with caveolin‐1 and has been implicated in PAH. Expression of eNOS increased at 48 hr and 1 wk post‐MCT with a significant loss at 3 wks post‐MCT. At 2 wks post‐MCT concomitant with PAH, the expression of eNOS activating molecules HSP90 and Akt was significantly reduced, which is consistent with impaired NO availability as observed previously. We conclude that there is progressive deregulation of multiple signaling pathways leading to cell proliferation, inhibition of apoptosis and NO impairment in PAH. This may in part, explain the difficulties encountered in the treatment of PAH.