In situ Evidence of Collagen V and Interleukin-6/Interleukin-17 Activation in Vascular Remodeling of Experimental Pulmonary Hypertension

Abstract

Several studies have reported the pathophysiologic and molecular mechanisms responsible for pulmonary arterial hypertension (PAH). However, the in situ evidence of collagen V (Col V) and interleukin-17 (IL-17)/interleukin-6 (IL-6) activation in PAH has not been fully elucidated. We analyzed the effects of collagen I (Col I), Col V, IL-6, and IL-17 on vascular remodeling and hemodynamics and its possible mechanisms of action in monocrotaline (MCT)-induced PAH. Twenty male Wistar rats were randomly divided into two groups. In the PAH group, animals received MCT 60 mg/kg intraperitoneally, whereas the control group (CTRL) received saline. On day 21, the pulmonary blood pressure (PAP) and right ventricular systolic pressure (RVSP) were determined. Lung histology (smooth muscle cell proliferation [alpha-smooth muscle actin; alpha-SMA] and periadventitial fibrosis), immunofluorescence (Col I, Col V, and alpha-SMA), immunohistochemistry (IL-6, IL-17, and transforming growth factor-beta [TGF-beta]), and transmission electron microscopy to detect fibronexus were evaluated. The RVSP (40 +/- 2 vs. 24 +/- 1 mm Hg, respectively; p < 0.0001), right ventricle hypertrophy index (65 +/- 9 and 25 +/- 5%, respectively; p < 0.0001), vascular periadventitial Col I and Col V, smooth muscle cell alpha-SMA+, fibronexus, IL-6, IL-17, and TGF-beta were higher in the MCT group than in the CTRL group. In conclusion, our findings indicate in situ evidence of Col V and IL-6/IL-17 activation in vascular remodeling and suggest that increase of Col V may yield potential therapeutic targets for treating patients with PAH.