Caveolae, caveolin and control of vascular tone: nitric oxide (NO) and endothelium derived hyperpolarizing factor (EDHF) regulation.
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.
Rath
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Unit of Pharmacology and Therapeutics, Universite Catholique de Louvain, UCL-FATH 5349, 52 Avenue E. Mounier, B-1200 Brussels, Belgium.
Dessy
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C
Feron
O
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D000818:Animals; D001685:Biological Factors / Q000378:metabolism / Q000502:physiology*; D021941:Caveolae / Q000502:physiology*; D022461:Caveolins / Q000502:physiology*; D006801:Humans; D051379:Mice; D009129:Muscle Tonus / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
D001685:Biological Factors; D022461:Caveolins; C067410:endothelium-dependent hyperpolarization factor; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III