Frid Maria G, Li Min, Gnanasekharan Meena, Burke Danielle L, Fragoso Miguel, Strassheim Derek, Sylman Joanna L, Stenmark Kurt R
Department of Pediatrics, University of Colorado Denver, Aurora, 80045, USA.
Am J Physiol Lung Cell Mol Physiol. 2009 Dec;297(6):L1059-72. doi: 10.1152/ajplung.90611.2008. Epub 2009 Sep 18.
All forms of chronic pulmonary hypertension (PH) are characterized by structural remodeling of the pulmonary artery (PA) media, a process previously attributed solely to changes in the phenotype of resident smooth muscle cells (SMC). However, recent experimental evidence in both systemic and pulmonary circulations suggests that other cell types, including circulating and local progenitors, contribute significantly to this process. The goal of this study was to determine if hypoxia-induced remodeling of distal PA (dPA) media involves the emergence of cells with phenotypic and functional characteristics distinct from those of resident dPA SMC and fibroblasts. In vivo, in contrast to the phenotypically uniform SMC composition of dPA media in control calves, the remodeled dPA media of neonatal calves with severe hypoxia-induced PH comprised cells exhibiting a distinct phenotype, including the expression of hematopoetic (CD45), leukocytic/monocytic (CD11b, CD14), progenitor (cKit), and motility-associated (S100A4) cell markers. Consistent with these in vivo observations, primary cell cultures isolated from dPA media of hypertensive calves yielded not only differentiated SMC, but also smaller, morphologically rhomboidal (thus termed here "R") cells that transiently expressed CD11b, constitutively expressed the mesenchymal cell marker type I procollagen, expressed high mRNA levels of progenitor cell markers cKit, CD34, CD73, as well as for inflammatory mediators, IL-6 and MCP-1, and, with time in culture, gained expression of a myofibroblast marker, alpha-SM-actin. R cells exhibited highly augmented proliferative, migratory, invasive, and potent promitogenic capabilities, which were due, at least in part, to the production of PDGFs, SDF-1/CXCL12, and S100A4. These data suggest that the cellular mechanisms of dPA remodeling include the emergence of cells with phenotypic and functional characteristics markedly distinct from those of resident dPA cells.
所有形式的慢性肺动脉高压（PH）都以肺动脉（PA）中膜的结构重塑为特征，这一过程以前仅归因于驻留平滑肌细胞（SMC）表型的变化。然而，最近在体循环和肺循环中的实验证据表明，其他细胞类型，包括循环祖细胞和局部祖细胞，对这一过程有显著贡献。本研究的目的是确定缺氧诱导的远端PA（dPA）中膜重塑是否涉及具有与驻留dPA SMC和成纤维细胞不同的表型和功能特征的细胞的出现。在体内，与对照小牛dPA中膜表型一致的SMC组成不同，患有严重缺氧诱导的PH的新生小牛的重塑dPA中膜包含表现出不同表型的细胞，包括造血（CD45）、白细胞/单核细胞（CD11b、CD14）、祖细胞（cKit）和运动相关（S100A4）细胞标志物的表达。与这些体内观察结果一致，从高血压小牛的dPA中膜分离的原代细胞培养物不仅产生了分化的SMC，还产生了较小的、形态为菱形的（因此在此称为“R”）细胞，这些细胞短暂表达CD11b，组成性表达间充质细胞标志物I型前胶原，表达祖细胞标志物cKit、CD34、CD73以及炎症介质IL-6和MCP-1的高mRNA水平，并且随着培养时间的延长，获得了肌成纤维细胞标志物α-SM-肌动蛋白的表达。R细胞表现出高度增强的增殖、迁移、侵袭和强大的促有丝分裂能力，这至少部分归因于PDGFs、SDF-1/CXCL12和S100A4的产生。这些数据表明，dPA重塑的细胞机制包括具有与驻留dPA细胞明显不同的表型和功能特征的细胞的出现。
