Unit of Pharmacology and Therapeutics, Universite Catholique de Louvain, UCL-FATH 5349, 52 Avenue E. Mounier, B-1200 Brussels, Belgium.
J Physiol Pharmacol. 2009 Oct;60 Suppl 4:105-9.
Endothelium plays a crucial role in the regulation of cardiovascular homeostasis through the release of vasoactive factors. Nitric oxide (NO) and endothelium-derived hyperpolarizing factors (EDHF) are the two major actors controlling the vasomotor tone. The endothelial nitric oxide synthase (eNOS) was reported in the mid 90ies to be under the control of caveolin, the structural protein of caveolae. Nowadays, a large body of evidence has confirmed that the caveolin/eNOS interaction was needed to prevent inadequate NO production under basal conditions but also to facilitate the integration of extracellular stimuli to intracellular NO signals. Compartmentation of key actors in the EDHF signaling pathway is now also proposed to take place into caveolae. Accordingly, caveolin-deficient animals revealed both an unopposed NO production promoting vessel dilation and a lack of EDHF-driven vasorelaxation. The transient receptor potential (TRP) channels are the link between caveolae and EDHF. Different TRP channels involved in the capacitative calcium entry were found to directly interact with caveolin-1 in endothelial cells. TRPC1 and TRPC4 form a complex with the endoplasmic reticulum IP3 receptor thereby optimizing calcium signaling. EDHF-driven vasodilation was documented to be altered in a TRPV4-deficient mouse model. The close vicinity between TRPV4 and SKCa channels in caveolae together with the gap-junctions subunits connexins support a role of these microdomains in the generation and propagation of EDHF to vascular smooth muscle cells. In conclusion, caveolae and caveolin are important control points in the control of blood pressure by the endothelium. This also highlights how any alteration in the caveolae integrity or caveolin abundance may lead to and/or exacerbate endothelial dysfunction and associated cardiovascular diseases.
内皮细胞通过释放血管活性因子在心血管稳态的调节中起着至关重要的作用。一氧化氮（NO）和内皮衍生超极化因子（EDHF）是控制血管舒缩张力的两个主要因素。内皮型一氧化氮合酶（eNOS）在 90 年代中期被报道受 caveolin 调控，caveolin 是 caveolae 的结构蛋白。如今，大量证据证实，caveolin/eNOS 相互作用不仅需要在基础条件下防止 NO 生成不足，还需要促进细胞外刺激与细胞内 NO 信号的整合。EDHF 信号通路的关键因素的分隔现在也被提出发生在 caveolae 中。相应地，caveolin 缺陷动物表现出不受抑制的 NO 生成促进血管扩张，以及缺乏 EDHF 驱动的血管舒张。瞬时受体电位（TRP）通道是 caveolae 和 EDHF 之间的联系。在血管内皮细胞中，参与电容性钙内流的不同 TRP 通道被发现与 caveolin-1 直接相互作用。TRPC1 和 TRPC4 与内质网 IP3 受体形成复合物，从而优化钙信号。在 TRPV4 缺陷小鼠模型中记录到 EDHF 驱动的血管舒张发生改变。TRPV4 和 SKCa 通道在 caveolae 中的紧密接近以及间隙连接亚基 connexins 支持这些微区在 EDHF 向血管平滑肌细胞的产生和传播中的作用。总之，caveolae 和 caveolin 是内皮细胞控制血压的重要控制点。这也强调了 caveolae 完整性或 caveolin 丰度的任何改变如何可能导致和/或加剧内皮功能障碍和相关心血管疾病。
