Primary Pulmonary Hypertension Is Associated With Reduced Pulmonary Vascular Expression of Type II Bone Morphogenetic Protein Receptor

TLDR

Primary pulmonary hypertension is frequently caused by mutations in the BMPR‑II receptor, yet the receptor’s normal and disease‑specific lung distribution had not been characterized. The study aimed to map BMPR‑II and related TGF‑β receptors in lung tissue from PPH, secondary PH, and donor controls. Immunohistochemistry and in situ hybridization identified BMPR‑II localization, and patients were genotyped for BMPR2 mutations. BMPR‑II is predominantly endothelial in normal lungs, but its expression is markedly reduced in peripheral vessels of PPH patients—especially those with heterozygous BMPR2 mutations—while secondary PH shows a lesser decrease, and TGF‑βRII and CD31 levels remain unchanged, suggesting reduced BMPR‑II contributes to vascular obliteration.

Abstract

Mutations in the type II receptor for bone morphogenetic protein (BMPR-II), a receptor member of the transforming growth factor-beta (TGF-beta) superfamily, underlie many familial and sporadic cases of primary pulmonary hypertension (PPH).Because the sites of expression of BMPR-II in the normal and hypertensive lung are unknown, we studied the cellular localization of BMPR-II and the related type I and II receptors for TGF-beta by immunohistochemistry in lung sections from patients undergoing heart-lung transplantation for PPH (n=11, including 3 familial cases) or secondary pulmonary hypertension (n=6) and from unused donor lungs (n=4). In situ hybridization was performed for BMPR-II mRNA. Patients were screened for the presence of mutations in BMPR2. In normal lungs, BMPR-II expression was prominent on vascular endothelium, with minimal expression in airway and arterial smooth muscle. In pulmonary hypertension cases, the intensity of BMPR-II immunostaining varied between lesions but involved endothelial and myofibroblast components. Image analysis confirmed that expression of BMPR-II was markedly reduced in the peripheral lung of PPH patients, especially in those harboring heterozygous BMPR2 mutations. A less marked reduction was also observed in patients with secondary pulmonary hypertension. In contrast, there was no difference in level of staining for TGF-betaRII or the endothelial marker CD31.The cellular localization of BMPR-II is consistent with a role in the formation of pulmonary vascular lesions in PPH, and reduced BMPR-II expression may contribute to the process of vascular obliteration in severe pulmonary hypertension.