Gu Sue, Mickael Claudia, Kumar Rahul, Lee Michael H, Sanders Linda, Kassa Biruk, Harral Julie, Williams Jason, Hansen Kirk C, Stenmark Kurt R, Tuder Rubin M, Graham Brian B
Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine University of Colorado Anschutz Medical Campus Aurora Colorado USA.
Cardiovascular Pulmonary Research Lab University of Colorado School of Medicine Aurora Colorado USA.
Pulm Circ. 2022 Jul 1;12(3):e12105. doi: 10.1002/pul2.12105. eCollection 2022 Jul.
Right ventricular (RV) failure is the primary cause of death in pulmonary hypertension (PH), but the mechanisms of RV failure are not well understood. We hypothesized macrophages in the RV contribute to the RV response in PH. We induced PH in mice with hypoxia (FiO 10%) and exposure, and in rats with SU5416-hypoxia. We quantified cardiac macrophages in mice using flow cytometry. Parabiosis between congenic CD45.1/.2 mice or Cx3cr1-green fluorescent protein and wild-type mice was used to quantify circulation-derived macrophages in experimental PH conditions. We administered clodronate liposomes to Sugen hypoxia (SU-Hx) exposed rats to deplete macrophages and evaluated the effect on the extracellular matrix (ECM) and capillary network in the RV. In hypoxia exposed mice, the overall number of macrophages did not significantly change but two macrophage subpopulations increased. Parabiosis identified populations of RV macrophages that at steady state is derived from the circulation, with one subpopulation that significantly increased with PH stimuli. Clodronate treatment of SU-Hx rats resulted in a change in the RV ECM, without altering the RV vasculature, and correlated with improved RV function. Populations of RV macrophages increase and contribute to RV remodeling in PH, including through regulation of the RV ECM.
右心室（RV）衰竭是肺动脉高压（PH）患者死亡的主要原因，但RV衰竭的机制尚不完全清楚。我们推测RV中的巨噬细胞在PH中参与了RV的反应。我们通过低氧（FiO₂ 10%）和暴露诱导小鼠发生PH，以及用SU5416-低氧诱导大鼠发生PH。我们使用流式细胞术对小鼠心脏巨噬细胞进行定量。利用同基因CD45.1/.2小鼠或Cx3cr1-绿色荧光蛋白小鼠与野生型小鼠间的联体生活来定量实验性PH条件下循环来源的巨噬细胞。我们给暴露于Sugen低氧（SU-Hx）的大鼠注射氯膦酸盐脂质体以清除巨噬细胞，并评估其对RV细胞外基质（ECM）和毛细血管网络的影响。在低氧暴露的小鼠中，巨噬细胞总数没有显著变化，但两个巨噬细胞亚群增加。联体生活实验确定了RV巨噬细胞群体在稳态时来源于循环，其中一个亚群在PH刺激下显著增加。对SU-Hx大鼠进行氯膦酸盐处理导致RV ECM发生变化，但未改变RV血管系统，且与RV功能改善相关。RV巨噬细胞群体增加并参与PH中的RV重塑，包括通过调节RV ECM来实现。
