Atkinson Carl, Stewart Susan, Upton Paul D, Machado Rajiv, Thomson Jennifer R, Trembath Richard C, Morrell Nicholas W
Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK.
Circulation. 2002 Apr 9;105(14):1672-8. doi: 10.1161/01.cir.0000012754.72951.3d.
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.
骨形态发生蛋白II型受体（BMPR-II）是转化生长因子-β（TGF-β）超家族的受体成员，其突变是许多家族性和散发性原发性肺动脉高压（PPH）病例的基础。
由于BMPR-II在正常肺和高血压肺中的表达位点尚不清楚，我们通过免疫组织化学研究了BMPR-II以及TGF-β相关的I型和II型受体在接受心肺移植的PPH患者（n = 11，包括3例家族性病例）或继发性肺动脉高压患者（n = 6）以及未使用的供体肺（n = 4）的肺切片中的细胞定位。对BMPR-II mRNA进行原位杂交。对患者进行BMPR2突变检测。在正常肺中，BMPR-II在血管内皮上表达突出，在气道和动脉平滑肌中表达极少。在肺动脉高压病例中，BMPR-II免疫染色强度在不同病变之间有所不同，但涉及内皮和成肌纤维细胞成分。图像分析证实，PPH患者外周肺中BMPR-II的表达明显降低，尤其是那些携带BMPR2杂合突变的患者。继发性肺动脉高压患者也观察到较不明显的降低。相比之下，TGF-βRII或内皮标志物CD31的染色水平没有差异。
BMPR-II的细胞定位与PPH中肺血管病变的形成作用一致，BMPR-II表达降低可能有助于严重肺动脉高压中血管闭塞的过程。
