The vascular-parenchymal crosstalk regulates lung fibrosis through BMPR2 and CTGF signaling

Abstract

Rationale: Idiopathic pulmonary fibrosis (IPF) causes pulmonary vascular remodelling and can develop pulmonary hypertension (PH), resulting in a poorer prognosis. We hypothesized that endothelial dysfunction and vascular remodelling in PH secondary to IPF enhance pro-fibrotic signals in the fibrotic lung and thereby actively contribute to the progression of interstitial fibrosis. Methods: The fibrosis model using adenoviral vector coding active TGF-I²1 was established by our group, and it induces persistent pulmonary fibrosis as well as substantial PH without much inflammation, different from bleomycin. Vascular endothelial cells (ECs) were sorted from rat lungs using flow cytometry. Primary vascular smooth muscle cells (VSMCs) were cultured from rat lungs. Results: The number of ECs was decreased in the fibrotic lung. VSMCs from remodeled pulmonary arteries (fVSMCs) had increased abilities to migrate, invade, and proliferate. Co-culture rat fibroblasts with fVSMCs induced fibrotic phenotype in fibroblasts. Conditioned media from fVSMCs also induced fibrotic phenotype in fibroblasts. The levels of Bmpr2 and its signaling, crucial for maintaining the viability of ECs and inhibition of VSMC proliferation, were decreased in ECs and VSMCs from the fibrotic lung. While the level of Ctgf, a key fibrogenic molecule that affects several signaling including Tgfb and Bmp, was increased. Administration of Tacrolimus to activate Bmpr2 signaling attenuated lung fibrosis as well as PH in rats. Conclusions: Endothelial dysfunction and vascular remodeling in PH secondary to pulmonary fibrosis enhance pro-fibrotic effects in the fibrotic lung through Bmpr2 and Ctgf signaling.