Schreier David, Hacker Timothy, Song Gouqing, Chesler Naomi
Department of Biomedical Engineering, University of Wisconsin, 2145 ECB, 1550 Engineering Drive, Madison, WI 53706, USA.
J Biomech Eng. 2013 Feb;135(2):021018. doi: 10.1115/1.4023480.
Pulmonary arterial hypertension (PAH) is a rapidly fatal disease in which mortality is typically due to right ventricular (RV) failure. An excellent predictor of mortality in PAH is proximal pulmonary artery stiffening, which is mediated by collagen accumulation in hypoxia-induced pulmonary hypertension (HPH) in mice. We sought to investigate the impact of limiting vascular and ventricular collagen accumulation on RV function and the hemodynamic coupling efficiency between the RV and pulmonary vasculature. Inbred mice were exposed to chronic hypoxia for 10 days with either no treatment (HPH) or with treatment with a proline analog that impairs collagen synthesis (CHOP-PEG; HPH + CP). Both groups were compared to control mice (CTL) exposed only to normoxia (no treatment). An admittance catheter was used to measure pressure-volume loops at baseline and during vena cava occlusion, with mice ventilated with either room air or 8% oxygen, from which pulmonary hemodynamics, RV function, and ventricular-vascular coupling efficiency (ηvvc) were calculated. Proline analog treatment limited increases in RV afterload (neither effective arterial elastance Ea nor total pulmonary vascular resistance significantly increased compared to CTL with CHOP-PEG), limited the development of pulmonary hypertension (CHOP-PEG reduced right ventricular systolic pressure by 10% compared to HPH, p < 0.05), and limited RV hypertrophy (CHOP-PEG reduced RV mass by 18% compared to HPH, p < 0.005). In an acutely hypoxic state, treatment improved RV function (CHOP-PEG increased end-systolic elastance Ees by 43%, p < 0.05) and maintained ηvvc at control, room air levels. CHOP-PEG also decreased lung collagen content by 12% measured biochemically compared to HPH (p < 0.01), with differences evident in large and small pulmonary arteries by histology. Our results demonstrate that preventing new collagen synthesis limits pulmonary hypertension development by reducing collagen accumulation in the pulmonary arteries that affect RV afterload. In particular, the proline analog limited structural and functional changes in distal pulmonary arteries in this model of early and somewhat mild pulmonary hypertension. We conclude that collagen plays an important role in small pulmonary artery remodeling and, thereby, affects RV structure and function changes induced by chronic hypoxia.
肺动脉高压（PAH）是一种迅速致命的疾病，其死亡率通常归因于右心室（RV）衰竭。PAH死亡率的一个极佳预测指标是近端肺动脉僵硬度增加，这是由小鼠缺氧诱导的肺动脉高压（HPH）中胶原蛋白积累介导的。我们试图研究限制血管和心室胶原蛋白积累对右心室功能以及右心室与肺血管系统之间血流动力学耦合效率的影响。将近交系小鼠暴露于慢性缺氧环境10天，一组不进行任何处理（HPH组），另一组用一种会损害胶原蛋白合成的脯氨酸类似物进行处理（CHOP - PEG组；HPH + CP组）。将这两组与仅暴露于常氧环境（不进行处理）的对照小鼠（CTL组）进行比较。使用导纳导管在基线和腔静脉闭塞期间测量压力 - 容积环，小鼠分别用室内空气或8%氧气进行通气，由此计算肺血流动力学、右心室功能以及心室 - 血管耦合效率（ηvvc）。脯氨酸类似物处理限制了右心室后负荷的增加（与CHOP - PEG处理的CTL组相比，有效动脉弹性Ea和总肺血管阻力均未显著增加），限制了肺动脉高压的发展（与HPH组相比，CHOP - PEG使右心室收缩压降低了10%，p < 0.05），并限制了右心室肥厚（与HPH组相比，CHOP - PEG使右心室质量降低了18%，p < 0.005）。在急性缺氧状态下，处理改善了右心室功能（CHOP - PEG使收缩末期弹性Ees增加了43%，p < 0.05），并将ηvvc维持在对照室内空气水平。与HPH组相比，通过生化方法测量，CHOP - PEG还使肺胶原蛋白含量降低了12%（p < 0.01），组织学检查显示在大、小肺动脉中差异明显。我们的结果表明，通过减少影响右心室后负荷的肺动脉中的胶原蛋白积累，防止新的胶原蛋白合成可限制肺动脉高压的发展。特别是，在这个早期且程度稍轻的肺动脉高压模型中，脯氨酸类似物限制了远端肺动脉的结构和功能变化。我们得出结论，胶原蛋白在小肺动脉重塑中起重要作用，从而影响慢性缺氧诱导的右心室结构和功能变化。
