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)

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Non-technical summary Shaker-type potassium channels are found on the smooth muscle cells of blood vessels in the brain and are important in keeping the blood vessels open or dilated. We show that a protein called PSD95, previously found in nerve cells, interacts with these potassium channels. PSD95 may act as a scaffold to ensure that the potassium channels are expressed in adequate numbers and in the right location on the smooth muscle cells. When we reduced the number of PSD95 proteins, we saw that the potassium channels were also reduced and the blood vessels were not as dilated compared to blood vessels with normal amounts of PSD95. This research may help us understand how abnormal constriction of blood vessels in the brain occurs in diseases such as high blood pressure and stroke.Abstract Postsynaptic density-95 (PSD95) is a 95 kDa scaffolding molecule in the brain that clusters postsynaptic proteins including ion channels, receptors, enzymes and other signalling partners required for normal cognition. The voltage-gated, Shaker-type K + (K V 1) channel is one key binding partner of PSD95 scaffolds in neurons. However, K V 1 channels composed of α1.2 and α1.5 pore-forming subunits also are expressed in the vascular smooth muscle cells (cVSMCs) of the cerebral circulation, although the identity of their molecular scaffolds is unknown. Since α1.2 contains a binding motif for PSD95, we explored the possibility that cVSMCs express PSD95 as a scaffold to promote K V 1 channel expression and cerebral vasodilatation. Cerebral arteries from Sprague-Dawley rats were isolated for analysis of PSD95 and K V 1 channel proteins. PSD95 was detected in cVSMCs and it co-immunoprecipitated and co-localized with the pore-forming α1.2 subunit of the K V 1 channel. Antisense-mediated knockdown of PSD95 profoundly reduced K V 1 channel expression and suppressed K V 1 current in patch-clamped cVSMCs. Loss of PSD95 also depolarized cVSMCs in pressurized cerebral arteries and induced a strong constriction associated with a loss of functional K V 1 channels. Our findings provide initial evidence that PSD95 is expressed in cVSMCs, and the K V 1 channel is one of its important binding partners. PSD95 appears to function as a critical 'dilator' scaffold in cerebral arteries by increasing the number of functional K V 1 channels at the plasma membrane. Abbreviations AKAP150, A-kinase anchoring protein 150; AS, antisense; CA, cerebral arteries; cVSMCs, cerebral vascular smooth muscle cells; E m , membrane potential; GK, guanylate kinase; IP, immunoprecipitate; MAGUK, membrane-associated guanylate kinase; NMDA, N -methyl-D-aspartate; NOS, nitric oxide synthase; PDZ, postsynaptic density-95, discs large, zonula occludens-1; PKA, protein kinase A; Psora, 5-(4-phenylalkoxypsoralen); PSD95, postsynaptic density protein-95; PSS, physiological salt solution; SAP97, synapse-associated protein 97; ScTx, stromatoxin; SH3, Src homology 3.

Rationale The effect of stem/progenitor cells on myocardial perfusion and clinical outcomes in patients with refractory angina (RFA) remains unclear because studies published to date have been small phase I-II trials. Objective We performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the effect of cell-based therapy in patients with RFA who were ineligible for coronary revascularization. Methods and Results Several data sources were searched from inception till September 2015, which yielded six studies. The outcomes pooled were indices of angina (anginal episodes, Canadian Cardiovascular Society [CCS] angina class, exercise tolerance, anti-anginal medications), myocardial perfusion, and clinical end-points. We combined the reported clinical outcomes (myocardial infarction, cardiac-related hospitalization, and mortality) into a composite end-point (MACE). Mean difference (MD), standardized mean differences (SMD), or odds ratio (OR) were calculated to assess relevant outcomes. Our analysis shows an improvement in anginal episodes (MD -7.81;95% CI, -15.22−-0.-41), use of anti-anginal medications (SMD -0.59;CI, -1.03−-0.14), CCS class (MD -0.58;CI, -1.00−-0.16), exercise tolerance (SMD 0.331;CI, 0.08−0.55), and myocardial perfusion (SMD -0.49;CI, -0.76−-0.21) and a decreased risk of MACE (OR 0.49;CI, 0.25−0.98) and arrhythmias (OR 0.25; 95% CI, 0.06−0.98) in cell-treated patients compared with patients on maximal medical therapy. Conclusions The present meta-analysis indicates that cell-based therapies are not only safe but also lead to an improvement in indices of angina, relevant clinical outcomes, and myocardial perfusion in patients with RFA. These encouraging results suggest that larger, phase III RCTs are in order to conclusively determine the effect of stem/progenitor cells in RFA.