Wall stretch is a major stimulus for the myogenic response of small arteries to pressure. Recent findings suggest that G protein‐coupled receptors can elicit a stretch response. Our aim was to determine if angiotensin II type 1 receptors (AT1R) in vascular smooth muscle cells (VSMC) exert mechanosensitivity and identify the downstream ion channel mediators of myogenic vasoconstriction. We used mice deficient in AT1R signaling molecules and putative ion channel targets, namely AT1R, angiotensinogen, TRPC6 channels or subtypes of the KCNQ (Kv7) gene family (KCNQ3, 4 or 5). We identified a mechano‐sensing mechanism in mesenteric arteries and the renal circulation that relies on coupling of the AT1R subtype a (AT1aR) to a Gq/11‐protein as a critical event to accomplish the myogenic response. The mechano‐activation occurs after block of AT1R, and in the absence of angiotensinogen or TRPC6. Activation of AT1aR suppresses XE991‐sensitive Kv channel currents in VSMCs, blocking these channels enhances mesenteric and renal myogenic tone. Although KCNQ3, 4 and 5 are expressed in VSMCs, XE991‐sensitive K+ current and myogenic contractions persist in arteries deficient in these channels. Our results provide evidence that myogenic responses of mouse mesenteric and renal arteries rely on ligand‐independent mechano‐activation of AT1aR. This signal relies on an ion channel distinct from TRPC6 or KCNQ3, 4 or 5. Grant Funding Source: Supported by Deutsche Forschungsgemeinschaft (DFG)
Abstract-Perivascular adipose tissue has been recognized unequivocally as a major player in the pathology of metabolic and cardiovascular diseases. Through its production of adipokines and the release of other thus far unidentified factors, this recently discovered adipose tissue modulates vascular regulation and the myogenic response. After the discovery of its ability to diminish the vessel's response to vasoconstrictors, a new paradigm established adipose-derived relaxing factor (ADRF) as a paracrine smooth muscle cells' potassium channel opener that could potentially help combat vascular dysfunction. This review will discuss the role of ADRF in vascular dysfunction in obesity and hypertension, the different potassium channels that can be activated by this factor, and describes new pharmacological tools that can mimic the ADRF effect and thus can be beneficial against vascular dysfunction in cardiovascular disease. [19][20][21][22] and are also observable on veins. 23 The release of ADRF from PVAT is strongly dependent on the concentration of Ca 2+ and seems to be dependent on the activation of intracellular pathways involving tyrosine kinase and protein kinase A. In contrast, perivascular nerve endings, notably presynaptic neuronal N-type Ca 2+ , Na + channels, calcitonin gene-related peptide, cannabinoid, and vanilloid receptors, do not play an important role in this process.4 Importantly, recent experiments have shown a dual role of PVAT in the initiation and progression of obesity. In effect, PVAT (similarly to endothelium) in animal and human models of hypertension, obesity, and metabolic syndrome becomes dysfunctional and loses its anticontractile properties, likely because of a decrease in PVRF release. 16,[24][25][26][27] It is, therefore, of utmost importance to determine the nature of PVRFs as well as its targets for the paracrine regulation of PVAT. PVRF: Potential CandidatesSeveral studies have tried to pinpoint the nature of PVRFs. The role of adiponectin as PVRF has been thus far inconclusive. Vessels from the aorta and mesenteric arteries of adiponectin-knockout mice have been initially shown to maintain their anticontractile properties. 16 In contrast, recent studies in mesenteric vessels of wild-type mice advance that the vasorelaxing and hyperpolarizing effects of adiponectin rely on the opening of maxi Ca 2+ -activated K + (BK Ca ) channels. 28,29 In addition, a factor that might be adiponectin is released after stimulation of rat and murine mesenteric arteries with β3 adrenoreceptor. This latter factor seems to exert its paracrine effect by activation of AMPK and opening of BK ca channels. 30 Similarly to adiponectin, leptin has also been proposed as a candidate for PVRF in a hypertension mouse model. 31 Leptin, however, is perhaps not ADRF in the systemic circulation because the PVAT of Zucker fa/fa rats that lack the leptin receptor still display anticontractile properties. 3 As mentioned above, angiotensin-1 to 7 and methyl palmitate are also proposed as PVRF. A study using aortas from...
The anti-contractile effect of perivascular adipose tissue (PVAT) is an important mechanism in the modulation of vascular tone in peripheral arteries. Recent evidence has implicated the XE991-sensitive voltage-gated KV (KCNQ) channels in the regulation of arterial tone by PVAT. However, until now the in vivo pharmacology of the involved vascular KV channels with regard to XE991 remains undetermined, since XE991 effects may involve Ca2+ activated BKCa channels and/or voltage-dependent KV1.5 channels sensitive to diphenyl phosphine oxide-1 (DPO-1). In this study, we tested whether KV1.5 channels are involved in the control of mesenteric arterial tone and its regulation by PVAT. Our study was also aimed at extending our current knowledge on the in situ vascular pharmacology of DPO-1 and XE991 regarding KV1.5 and BKCa channels, in helping to identify the nature of K+ channels that could contribute to PVAT-mediated relaxation. XE991 at 30 μM reduced the anti-contractile response of PVAT, but had no effects on vasocontraction induced by phenylephrine (PE) in the absence of PVAT. Similar effects were observed for XE991 at 0.3 μM, which is known to almost completely inhibit mesenteric artery VSMC KV currents. 30 μM XE991 did not affect BKCa currents in VSMCs. Kcna5−/− arteries and wild-type arteries incubated with 1 μM DPO-1 showed normal vasocontractions in response to PE in the presence and absence of PVAT. KV current density and inhibition by 30 μM XE991 were normal in mesenteric artery VSMCs isolated from Kcna5−/− mice. We conclude that KV channels are involved in the control of arterial vascular tone by PVAT. These channels are present in VSMCs and very potently inhibited by the KCNQ channel blocker XE991. BKCa channels and/or DPO-1 sensitive KV1.5 channels in VSMCs are not the downstream mediators of the XE991 effects on PVAT-dependent arterial vasorelaxation. Further studies will need to be undertaken to examine the role of other KV channels in the phenomenon.
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