Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4Z6, Canada.
Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA.
Sci Rep. 2019 Jan 24;9(1):481. doi: 10.1038/s41598-018-36564-0.
The role of the smoothelin-like 1 (SMTNL1) protein in mediating vascular smooth muscle contractile responses to intraluminal pressure was examined in resistance vessels. Mesenteric arterioles from wild type (WT) and SMTNL1 global knock-out (KO) mice were examined with pressure myography. SMTNL1 deletion was associated with enhanced myogenic tone in vessels isolated from male, but not female, mice. Intraluminal pressures greater than 40 mmHg generated statistically significant differences in myogenic reactivity between WT and KO vessels. No overt morphological differences were recorded for vessels dissected from KO animals, but SMTNL1 deletion was associated with loss of myosin phosphatase-targeting protein MYPT1 and increase in the myosin phosphatase inhibitor protein CPI-17. Additionally, we observed altered contractile responses of isolated arteries from SMTNL1 KO mice to phenylephrine, KCl-dependent membrane depolarization and phorbol 12,13-dibutyrate (PDBu). Using pharmacological approaches, myogenic responses of both WT and KO vessels were equally affected by Rho-associated kinase (ROCK) inhibition; however, augmented protein kinase C (PKC) signaling was found to contribute to the increased myogenic reactivity of SMTNL1 KO vessels across the 60-120 mmHg pressure range. Based on these findings, we conclude that deletion of SMTNL1 contributes to enhancement of pressure-induced contractility of mesenteric resistance vessels by influencing the activity of myosin phosphatase.
平滑肌蛋白 1（SMTNL1）在介导血管平滑肌对腔内压力的收缩反应中的作用在阻力血管中进行了研究。用压力描记术检查了来自野生型（WT）和 SMTNL1 全局敲除（KO）小鼠的肠系膜小动脉。SMTNL1 缺失与雄性而非雌性小鼠分离的血管中的肌源性张力增强有关。腔内压力大于 40mmHg 时，WT 和 KO 血管之间的肌源性反应有统计学显著差异。从 KO 动物分离的血管没有明显的形态差异，但 SMTNL1 缺失与肌球蛋白磷酸酶靶向蛋白 MYPT1 的丢失和肌球蛋白磷酸酶抑制剂蛋白 CPI-17 的增加有关。此外，我们观察到 SMTNL1 KO 小鼠分离的动脉对苯肾上腺素、KCl 依赖性膜去极化和佛波醇 12,13-二丁酸酯（PDBu）的收缩反应发生改变。使用药理学方法，WT 和 KO 血管的肌源性反应均受 Rho 相关激酶（ROCK）抑制的同等影响；然而，发现蛋白激酶 C（PKC）信号增强有助于 SMTNL1 KO 血管在 60-120mmHg 压力范围内增加肌源性反应。基于这些发现，我们得出结论，SMTNL1 的缺失通过影响肌球蛋白磷酸酶的活性，导致肠系膜阻力血管中压力诱导的收缩性增强。
