Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor

C Atkinson, S Stewart, PD Upton, R Machado… - Circulation, 2002 - Am Heart Assoc
C Atkinson, S Stewart, PD Upton, R Machado, JR Thomson, RC Trembath, NW Morrell
Circulation, 2002Am Heart Assoc
Background—Mutations in the type II receptor for bone morphogenetic protein (BMPR-II), a
receptor member of the transforming growth factor-β (TGF-β) superfamily, underlie many
familial and sporadic cases of primary pulmonary hypertension (PPH). Methods and Results—
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-β by immunohistochemistry in lung sections from patients undergoing …
Background Mutations in the type II receptor for bone morphogenetic protein (BMPR-II), a receptor member of the transforming growth factor-β (TGF-β) superfamily, underlie many familial and sporadic cases of primary pulmonary hypertension (PPH).
Methods and Results 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-β 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-βRII or the endothelial marker CD31.
Conclusions 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.
Am Heart Assoc