Three-Dimensional Reconstruction of Pulmonary Arteries in Plexiform Pulmonary Hypertension Using Cell-Specific Markers

Abstract

The plexiform lesions of severe pulmonary hypertension (PH) are complex vascular structures composed primarily of endothelial cells. In this study, we use immunohistochemical markers to identify the various cell layers of pulmonary vessels and to identify different endothelial cell phenotypes in pulmonary arteries affected by severe PH. Our computerized three-dimensional reconstructions of nine vessels in five patients with severe PH demonstrate that plexiform (n = 14) and concentric-obliterative (n = 6) lesions occur distal to branch points of small pulmonary arteries. And, whereas plexiform lesions occur as solitary lesions, concentric-obliterative lesions appear to be only associated with, and proximal to, plexiform structures. The endothelial cells of plexiform lesions express intensely and uniformly the vascular endothelial growth factor (VEGF) receptor KDR and segregate phenotypically into cyclin-kinase inhibitor p27/kip1-negative cells in the central core of the plexiform lesion and p27/kip1-positive cells in peripheral areas adjacent to incipient blood vessel formation. Using immunohistochemistry and three-dimensional reconstruction techniques, we show that plexiform lesions are dynamic vascular structures characterized by at least two endothelial cell phenotypes. Plexiform arteriopathy is not merely an end stage or postthrombotic change--it may represent one stage in an ongoing, angiogenic endothelial cell growth process.

Pathology of Pulmonary Hypertension

“…These lesions are characteristic of in severe PH, as they significantly reduce significantly the luminal area. We documented the presence of concentric lesions in vascular segments proximal to plexiform lesions [11], suggesting that the concentric lesions arise from remodeled plexiform lesions. Concentric lesions composed of smooth muscle cells have also been described [12].…”

“…Plexiform lesions, typically located in branching pointes of muscular arteries [11], consists of a network of vascular channels lined up by endothelial cells [16] (Figures 1 and 2) and a core of myofibroblastic or less well-differentiated cells (Figure 3) [17]. In our experience, these lesions are characteristically found in cases of severe PH, including IPAH, and PH associated with HIV infection, liver cirrhosis, CREST, congenital heart malformations, and schistosomiasis.…”

Intrapulmonary vascular dilatations are common in portopulmonary hypertension and may be associated with decreased survival

“…Similarly, dilated arterial segments have been observed proximal to plexogenic vascular lesions in PAH with and without liver disease. [7][8][9][10] The natural history of IPVD identified in patients with POPH is unclear and may be impacted by vasodilator therapy. It is interesting that 3 patients did not have evidence of persistent IPVD on follow-up cTTE.…”

“…Symptoms include dyspnea, along with signs of right heart failure. [6][7][8][9][10] LT in POPH has been complicated by intraoperative mortality and variable postoperative outcomes. The primary focus of therapy is on control of pulmonary pressures with vasodilator therapy and improved right ventricle (RV) function, with consideration of LT if MPAP of 35 mm Hg or lower can be maintained.…”

Novel promoter and exon mutations of the BMPR2 gene in Chinese patients with pulmonary arterial hypertension

“…2 The development of PAH mainly affects small pulmonary arteries in which there is intense remodeling resulting in intimal thickening and medial hypertrophy because of an abnormal proliferation of smooth muscle and endothelial cells. 3,4 The most significant advance in understanding the pathogenesis of PAH has been the demonstration of germline mutations in the familial form of this disease that have been mapped to a single locus designated PPH1 (OMIM 178600) on chromosome 2q31 -32. 5 Subsequently, two independent groups identied heterozygous germline mutations in the gene encoding the bone morphogenetic protein type II receptor (BMPR2), a member of the transforming growth factor (TGF)-b superfamily of transmembrane serine/threonine kinase receptors, in patients with familial PAH (FPAH).…”