Department of Mechanical Engineering, University of Colorado at Boulder, USA.
Am J Physiol Lung Cell Mol Physiol. 2013 Jan 1;304(1):L70-81. doi: 10.1152/ajplung.00342.2012. Epub 2012 Oct 19.
Proximal arterial stiffening is an important predictor of events in systemic and pulmonary hypertension, partly through its contribution to downstream vascular abnormalities. However, much remains undetermined regarding the mechanisms involved in the vascular changes induced by arterial stiffening. We therefore addressed the hypothesis that high pulsatility flow, caused by proximal arterial stiffening, induces downstream pulmonary artery endothelial cell (EC) dysfunction that in turn leads to phenotypic change of smooth muscle cells (SMCs). To test the hypothesis, we employed a model pulmonary circulation in which upstream compliance regulates the pulsatility of flow waves imposed onto a downstream vascular mimetic coculture composed of pulmonary ECs and SMCs. The effects of high pulsatility flow on SMCs were determined both in the presence and absence of ECs. In the presence of ECs, high pulsatility flow increased SMC size and expression of the contractile proteins, smooth muscle α-actin (SMA) and smooth muscle myosin heavy chain (SM-MHC), without affecting proliferation. In the absence of ECs, high pulsatility flow decreased SMC expression of SMA and SM-MHC, without affecting SMC size or proliferation. To identify the molecular signals involved in the EC-mediated SMC responses, mRNA and/or protein expression of vasoconstrictors [angiotensin-converting enzyme (ACE) and endothelin (ET)-1], vasodilator (eNOS), and growth factor (TGF-β1) in EC were examined. Results showed high pulsatility flow decreased eNOS and increased ACE, ET-1, and TGF-β1 expression. ACE inhibition with ramiprilat, ET-1 receptor inhibition with bosentan, and treatment with the vasodilator bradykinin prevented flow-induced, EC-dependent SMC changes. In conclusion, high pulsatility flow stimulated SMC hypertrophy and contractile protein expression by altering EC production of vasoactive mediators and cytokines, supporting the idea of a coupling between proximal vascular stiffening, flow pulsatility, and downstream vascular function.
近段动脉僵硬是全身和肺动脉高压事件的一个重要预测因子，部分原因是其对下游血管异常的贡献。然而，关于动脉僵硬引起的血管变化涉及的机制，仍有许多尚未确定。因此，我们提出了这样一个假设：近端动脉僵硬引起的高脉动流导致下游肺动脉内皮细胞（EC）功能障碍，进而导致平滑肌细胞（SMC）表型改变。为了验证这一假设，我们采用了一种模型肺循环，其中上游顺应性调节施加于由肺 EC 和 SMC 组成的下游血管模拟共培养物的脉动流波的脉动性。在存在和不存在 EC 的情况下，确定了高脉动流对 SMC 的影响。在存在 EC 的情况下，高脉动流增加了 SMC 的大小和收缩蛋白，平滑肌α-肌动蛋白（SMA）和平滑肌肌球蛋白重链（SM-MHC）的表达，而不影响增殖。在不存在 EC 的情况下，高脉动流降低了 SMC 对 SMA 和 SM-MHC 的表达，而不影响 SMC 的大小或增殖。为了确定涉及 EC 介导的 SMC 反应的分子信号，检查了 EC 中血管收缩剂[血管紧张素转换酶（ACE）和内皮素（ET）-1]、血管扩张剂（eNOS）和生长因子（TGF-β1）的 mRNA 和/或蛋白表达。结果表明，高脉动流降低了 eNOS 并增加了 ACE、ET-1 和 TGF-β1 的表达。用雷米普利抑制 ACE、用波生坦抑制 ET-1 受体以及用血管扩张剂缓激肽处理可防止流量引起的、依赖 EC 的 SMC 变化。总之，高脉动流通过改变 EC 产生的血管活性介质和细胞因子，刺激 SMC 肥大和收缩蛋白表达，支持近端血管僵硬、流量脉动性和下游血管功能之间存在耦合的观点。
