Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI, United States.
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, United States.
Front Endocrinol (Lausanne). 2022 Aug 31;13:995499. doi: 10.3389/fendo.2022.995499. eCollection 2022.
During hypertension, vascular remodeling allows the blood vessel to withstand mechanical forces induced by high blood pressure (BP). This process is well characterized in the media and intima layers of the vessel but not in the perivascular adipose tissue (PVAT). In PVAT, there is evidence for fibrosis development during hypertension; however, PVAT remodeling is poorly understood. In non-PVAT depots, mechanical forces can affect adipogenesis and lipogenic stages in preadipocytes. In tissues exposed to high magnitudes of pressure like bone, the activation of the mechanosensor PIEZO1 induces differentiation of progenitor cells towards osteogenic lineages. PVAT's anatomical location continuously exposes it to forces generated by blood flow that could affect adipogenesis in normotensive and hypertensive states. In this study, we hypothesize that activation of PIEZO1 reduces adipogenesis in PVAT preadipocytes. The hypothesis was tested using pharmacological and mechanical activation of PIEZO1. Thoracic aorta PVAT (APVAT) was collected from 10-wk old male SD rats (n=15) to harvest preadipocytes that were differentiated to adipocytes in the presence of the PIEZO1 agonist Yoda1 (10 µM). Mechanical stretch was applied with the FlexCell System at 12% elongation, half-sine at 1 Hz simultaneously during the 4 d of adipogenesis (MS+, mechanical force applied; MS-, no mechanical force used). Yoda1 reduced adipogenesis by 33% compared with CON and, as expected, increased cytoplasmic Ca2+ flux. MS+ reduced adipogenesis efficiency compared with MS-. When expression was blocked with siRNA [si; NC=non-coding siRNA], the anti-adipogenic effect of Yoda1 was reversed in si cells but not in NC; in contrast, si did not alter the inhibitory effect of MS+ on adipogenesis. These data demonstrate that PIEZO1 activation in PVAT reduces adipogenesis and lipogenesis and provides initial evidence for an adaptive response to excessive mechanical forces in PVAT during hypertension.
在高血压期间，血管重塑使血管能够承受高血压（BP）引起的机械力。这个过程在血管的中膜和内膜层中得到了很好的描述，但在血管周围脂肪组织（PVAT）中却没有。在 PVAT 中，有证据表明在高血压期间会发生纤维化发展；然而，PVAT 重塑的机制尚不清楚。在非 PVAT 部位，机械力可以影响前脂肪细胞的脂肪生成和脂肪生成阶段。在像骨骼这样暴露于高压力的组织中，机械感受器 PIEZO1 的激活会诱导祖细胞向成骨谱系分化。PVAT 的解剖位置使其不断暴露于血流产生的力中，这些力可能会影响正常血压和高血压状态下的脂肪生成。在这项研究中，我们假设 PIEZO1 的激活会减少 PVAT 前脂肪细胞的脂肪生成。该假说通过药理学和机械激活 PIEZO1 进行了测试。从 10 周龄雄性 SD 大鼠（n=15）收集胸主动脉 PVAT（APVAT），以收获前脂肪细胞，然后在 PIEZO1 激动剂 Yoda1（10 µM）的存在下分化为脂肪细胞。在 4 天的脂肪生成过程中（MS+，施加机械力；MS-，不使用机械力），同时以 12%的伸长率和半正弦波应用 FlexCell 系统进行机械拉伸。与 CON 相比，Yoda1 使脂肪生成减少了 33%，并如预期的那样增加了细胞质 Ca2+通量。与 MS-相比，MS+降低了脂肪生成效率。当用 siRNA [si；NC=非编码 siRNA]阻断 表达时，Yoda1 的抗脂肪生成作用在 si 细胞中被逆转，但在 NC 中没有逆转；相反，si 并没有改变 MS+对脂肪生成的抑制作用。这些数据表明，PVAT 中的 PIEZO1 激活可减少脂肪生成和脂肪生成，并为高血压期间 PVAT 中过度机械力的适应性反应提供了初步证据。
