Identification of the Muscarinic Acetylcholine Receptor Subtype Mediating Cholinergic Vasodilation in Murine Retinal Arterioles

Gericke, Adrian; Sniatecki, Jan J.; Goloborodko, Evgeny; Steege, Andreas; Zavaritskaya, Olga; Vetter, Jan M.; Grus, Franz H.; Patzak, Andreas; Wess, Jürgen; Pfeiffer, Norbert

doi:10.1167/iovs.11-7370

Cited by 43 publications

(43 citation statements)

References 38 publications

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“…This would be in line with the concept that specific portions of the cellular eNOS pool are preassembled into larger signaling complexes, allowing for controlled spatial activation or local NO production. 4,18 Although endothelial cells express the M3R and acetylcholine is routinely used in in vitro studies to assess endothelial cell function and NO production, [8][9][10][11][12][13] there is considerable debate about the in vivo relevance of acetylcholine for the regulation of vascular tone and resistance. Indeed, acetylcholine is produced by perivascular nerve fibers, but they are restricted to some arterial vascular beds.…”

Section: Discussionmentioning

confidence: 99%

The F-BAR Protein NOSTRIN Dictates the Localization of the Muscarinic M3 Receptor and Regulates Cardiovascular Function

Kovačević

Müller

Kojonazarov

et al. 2015

Circulation Research

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Rationale: Endothelial dysfunction is an early event in cardiovascular disease and characterized by reduced production of nitric oxide (NO). The F-BAR protein NO synthase traffic inducer (NOSTRIN) is an interaction partner of endothelial NO synthase and modulates its subcellular localization, but the role of NOSTRIN in pathophysiology in vivo is unclear. Objective: We analyzed the consequences of deleting the NOSTRIN gene in endothelial cells on NO production and cardiovascular function in vivo using NOSTRIN knockout mice. Methods and Results: The levels of NO and cGMP were significantly reduced in mice with endothelial cell–specific deletion of the NOSTRIN gene resulting in diastolic heart dysfunction. In addition, systemic blood pressure was increased, and myograph measurements indicated an impaired acetylcholine-induced relaxation of isolated aortic rings and resistance arteries. We found that the muscarinic acetylcholine receptor subtype M3 (M3R) interacted directly with NOSTRIN, and the latter was necessary for correct localization of the M3R at the plasma membrane in murine aorta. In the absence of NOSTRIN, the acetylcholine-induced increase in intracellular Ca 2+ in primary endothelial cells was abolished. Moreover, the activating phosphorylation and Golgi translocation of endothelial NO synthase in response to the M3R agonist carbachol were diminished. Conclusions: NOSTRIN is crucial for the localization and function of the M3R and NO production. The loss of NOSTRIN in mice leads to endothelial dysfunction, increased blood pressure, and diastolic heart failure.

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Section: Discussionmentioning

confidence: 99%

The F-BAR Protein NOSTRIN Dictates the Localization of the Muscarinic M3 Receptor and Regulates Cardiovascular Function

Kovačević

Müller

Kojonazarov

et al. 2015

Circulation Research

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“…While most of the vasoactive neurotransmitters are released by variety of neurons, only ACh is selectively released by a well-characterized population of neurons-cholinergic amacrine cells [27,28]. The vasodilatory effect of ACh on retinal capillaries and arterioles has been well established [18,[29][30][31].…”

Section: Neuronal Control Of Blood Flow: a Role For Cholinergic Regulmentioning

confidence: 99%

“…Consistently, cholinergic vasodilation of murine retinal arterioles was also shown to be primarily mediated by NO, since blockade of NO production almost completely abolished responses to ACh. When endothelial cells were damaged, there was no dilation, but vasoconstriction was present [31]. It is likely that ACh released from cholinergic cells binds to muscarinic receptors found on pericytes and endothelial cells and stimulates NO production in the endothelial cells.…”

Section: Neuronal Control Of Blood Flow: a Role For Cholinergic Regulmentioning

confidence: 99%

“…They express functional receptors for a variety of synaptic transmitters, which can cause contraction or relaxation [15,18,50]. For example, application of ACh alters the membrane potential of pericytes, leading to cell contraction and constriction of the blood vessel [18,31]. Thus, it is possible that the cholinergic cells may modulate blood vessel diameter via pericytes to modulate blood flow, though further investigation is needed to confirm this.…”

Section: Neuronal Control Of Blood Flow: a Role For Cholinergic Regulmentioning

confidence: 99%

“…Muscarinic ACh receptors (type M3) are present in retinal vasculature and are essential for vasodilation [29,31,52]. Indeed, application of 100 μM carbachol, a nondegradable analogue of ACh, resulted in significant dilation in both capillaries and precapillary arterioles (see Fig.…”

Section: Optogenetic Control Of a Defined Neural Circuit: A Strategy mentioning

confidence: 99%

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Leveraging Optogenetic-Based Neurovascular Circuit Characterization for Repair

2016

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Optogenetic techniques are a powerful tool for determining the role of individual functional components within complex neural circuits. By genetically targeting specific cell types, neural mechanisms can be actively manipulated to gain a better understanding of their origin and function, both in health and disease. The potential of optogenetics is not limited to answering biological questions, as it is also a promising therapeutic approach for neurological diseases. An important prerequisite for this approach is to have an identified target with a uniquely defined role within a given neural circuit. Here, we examine the retinal neurovascular unit, a circuit that incorporates neurons and vascular cells to control blood flow in the retina. We highlight the role of a specific cell type, the cholinergic amacrine cell, in modulating vascular cells, and demonstrate how this can be targeted and controlled with optogenetics. A better understanding of these mechanisms will not only extend our understanding of neurovascular interactions in the brain, but ultimately may also provide new targets to treat vision loss in a variety of retinal diseases.

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Ablation of lysozyme M-positive cells prevents aircraft noise-induced vascular damage without improving cerebral side effects

et al. 2021

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Aircraft noise induces vascular and cerebral inflammation and oxidative stress causing hypertension and cardiovascular/cerebral dysfunction. With the present studies, we sought to determine the role of myeloid cells in the vascular vs. cerebral consequences of exposure to aircraft noise. Toxin-mediated ablation of lysozyme M+ (LysM+) myeloid cells was performed in LysMCreiDTR mice carrying a cre-inducible diphtheria toxin receptor. In the last 4d of toxin treatment, the animals were exposed to noise at maximum and mean sound pressure levels of 85 and 72 dB(A), respectively. Flow cytometry analysis revealed accumulation of CD45+, CD11b+, F4/80+, and Ly6G−Ly6C+ cells in the aortas of noise-exposed mice, which was prevented by LysM+ cell ablation in the periphery, whereas brain infiltrates were even exacerbated upon ablation. Aircraft noise-induced increases in blood pressure and endothelial dysfunction of the aorta and retinal/mesenteric arterioles were almost completely normalized by ablation. Correspondingly, reactive oxygen species in the aorta, heart, and retinal/mesenteric vessels were attenuated in ablated noise-exposed mice, while microglial activation and abundance in the brain was greatly increased. Expression of phagocytic NADPH oxidase (NOX-2) and vascular cell adhesion molecule-1 (VCAM-1) mRNA in the aorta was reduced, while NFκB signaling appeared to be activated in the brain upon ablation. In sum, we show dissociation of cerebral and peripheral inflammatory reactions in response to aircraft noise after LysM+ cell ablation, wherein peripheral myeloid inflammatory cells represent a dominant part of the pathomechanism for noise stress-induced cardiovascular effects and their central nervous counterparts, microglia, as key mediators in stress responses.

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Identification of the Muscarinic Acetylcholine Receptor Subtype Mediating Cholinergic Vasodilation in Murine Retinal Arterioles

Abstract: These findings provide evidence that endothelial M(3) receptors mediate cholinergic vasodilation in murine retinal arterioles via activation of NO synthase.

Cited by 43 publications

References 38 publications

The F-BAR Protein NOSTRIN Dictates the Localization of the Muscarinic M3 Receptor and Regulates Cardiovascular Function

The F-BAR Protein NOSTRIN Dictates the Localization of the Muscarinic M3 Receptor and Regulates Cardiovascular Function

Leveraging Optogenetic-Based Neurovascular Circuit Characterization for Repair

Ablation of lysozyme M-positive cells prevents aircraft noise-induced vascular damage without improving cerebral side effects

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