Cooperative action of APJ and α1A-adrenergic receptor in vascular smooth muscle cells induces vasoconstriction

Nagano, Katsumasa; Kwon, Chulwon; Ishida, Junji; Hashimoto, Tatsuo; Kim, Jun-Dal; Kishikawa, Nana; Murao, Mei; Kimura, Kenjiro; Kasuya, Yoshitoshi; Kimura, Sadao; Chen, Yi Ching; Tsuchimochi, Hirotsugu; Shirai, Masamitsu; Pearson, James T.; Fukamizu, Akiyoshi

doi:10.1093/jb/mvz071

Cited by 14 publications

(6 citation statements)

References 38 publications

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“…Apelin acts via binding to G-proteincoupled-receptors known as APJ receptors, which are widely expressed throughout the cardiovascular system (Katugampola et al, 2001;Kleinz et al, 2005;Pitkin et al, 2010;Luo et al, 2018). An increasing body of evidence indicates that the apelin-APJ receptor signaling system regulates vascular function in mammalian arteries and veins (Gurzu et al, 2006;Jia et al, 2007;Salcedo et al, 2007;Wang et al, 2016;Nagano et al, 2019), including those from humans (Katugampola et al, 2001;Kleinz and Davenport, 2004;Maguire et al, 2009;Schinzari et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Apelin Does Not Impair Coronary Artery Relaxation Mediated by Nitric Oxide-Induced Activation of BKCa Channels

2021

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Apelin-APJ receptor signaling regulates vascular tone in cerebral and peripheral arteries. We recently reported that apelin inhibits BKCa channel function in cerebral arteries, resulting in impaired endothelium-dependent relaxations. In contrast, apelin causes endothelium-dependent relaxation of coronary arteries. However, the effects of apelin on BKCa channel function in coronary arterial myocytes have not yet been explored. We hypothesized that apelin-APJ receptor signaling does not have an inhibitory effect on coronary arterial BKCa channels and hence does not alter nitric oxide (NO)-dependent relaxation of coronary arteries. Patch clamp recording was used to measure whole cell K+ currents in freshly isolated coronary smooth muscle cells. Apelin had no effect on the increases in current density in response to membrane depolarization or to NS1619 (a BKCa channel opener). Moreover, apelin did not inhibit NO/cGMP-dependent relaxations that required activation of BKCa channels in isolated coronary arteries. Apelin-APJ receptor signaling caused a marked increase in intracellular Ca2+ levels in coronary arterial smooth muscle cells, but failed to activate PI3-kinase to increase phosphorylation of Akt protein. Collectively, these data provide mechanistic evidence that apelin has no inhibitory effects on BKCa channel function in coronary arteries. The lack of inhibitory effect on BKCa channels makes it unlikely that activation of APJ receptors in coronary arteries would adversely affect coronary flow by creating a vasoconstrictive environment. It can be expected that apelin or other APJ receptor agonists in development will not interfere with the vasodilator effects of endogenous BKCa channel openers.

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Section: Introductionmentioning

confidence: 99%

Apelin Does Not Impair Coronary Artery Relaxation Mediated by Nitric Oxide-Induced Activation of BKCa Channels

2021

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“…The synergistic effects of the other receptors may have profound implications on the pathogenesis of AD and CAA. For example, the vasoconstriction generated by agonists of the α 1A -ARs is enhanced by stimulation of the apelin receptor [26]. Genetic deficiency of the α 2A -AR significantly reduces Aβ generation, whereas stimulation of this receptor enhances it [27].…”

Section: Discussionmentioning

confidence: 99%

Vascular α1A Adrenergic Receptors as a Potential Therapeutic Target for IPAD in Alzheimer’s Disease

et al. 2020

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Drainage of interstitial fluid from the brain occurs via the intramural periarterial drainage (IPAD) pathways along the basement membranes of cerebral capillaries and arteries against the direction of blood flow into the brain. The cerebrovascular smooth muscle cells (SMCs) provide the motive force for driving IPAD, and their decrease in function may explain the deposition of amyloid-beta as cerebral amyloid angiopathy (CAA), a key feature of Alzheimer’s disease. The α-adrenoceptor subtype α1A is abundant in the brain, but its distribution in the cerebral vessels is unclear. We analysed cultured human cerebrovascular SMCs and young, old and CAA human brains for (a) the presence of α1A receptor and (b) the distribution of the α1A receptor within the cerebral vessels. The α1A receptor was present on the wall of cerebrovascular SMCs. No significant changes were observed in the vascular expression of the α1A-adrenergic receptor in young, old and CAA cases. The pattern of vascular staining appeared less punctate and more diffuse with ageing and CAA. Our results show that the α1A-adrenergic receptor is preserved in cerebral vessels with ageing and in CAA and is expressed on cerebrovascular smooth muscle cells, suggesting that vascular adrenergic receptors may hold potential for therapeutic targeting of IPAD.

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“…Its activation causes stimulation of PLC-β, which cleaves PIP2 into DAG and IP3. This increased intracellular IP3 binds to its receptors, leading to higher iCa 2+ levels and subsequent myosin phosphorylation ( 250 , 251 ). The result of this pathway is a peripheral vasoconstriction that reverses peripheral vasodilation alleviating hypotension and reducing edema ( 252 , 253 ).…”

Section: Treatmentmentioning

confidence: 99%

Pathophysiological, Cellular, and Molecular Events of the Vascular System in Anaphylaxis

et al. 2022

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Anaphylaxis is a systemic hypersensitivity reaction that can be life threatening. Mechanistically, it results from the immune activation and release of a variety of mediators that give rise to the signs and symptoms of this pathological event. For years, most of the research in anaphylaxis has focused on the contribution of the immune component. However, approaches that shed light on the participation of other cellular and molecular agents are necessary. Among them, the vascular niche receives the various signals (e.g., histamine) that elicit the range of anaphylactic events. Cardiovascular manifestations such as increased vascular permeability, vasodilation, hypotension, vasoconstriction, and cardiac alterations are crucial in the pathophysiology of anaphylaxis and are highly involved to the development of the most severe cases. Specifically, the endothelium, vascular smooth muscle cells, and their molecular signaling outcomes play an essential role downstream of the immune reaction. Therefore, in this review, we synthesized the vascular changes observed during anaphylaxis as well as its cellular and molecular components. As the risk of anaphylaxis exists both in clinical procedures and in routine life, increasing our knowledge of the vascular physiology and their molecular mechanism will enable us to improve the clinical management and how to treat or prevent anaphylaxis.Key MessageAnaphylaxis, the most severe allergic reaction, involves a variety of immune and non-immune molecular signals that give rise to its pathophysiological manifestations. Importantly, the vascular system is engaged in processes relevant to anaphylactic events such as increased vascular permeability, vasodilation, hypotension, vasoconstriction, and decreased cardiac output. The novelty of this review focuses on the fact that new studies will greatly improve the understanding of anaphylaxis when viewed from a vascular molecular angle and specifically from the endothelium. This knowledge will improve therapeutic options to treat or prevent anaphylaxis.

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Cooperative action of APJ and α1A-adrenergic receptor in vascular smooth muscle cells induces vasoconstriction

Cited by 14 publications

References 38 publications

Apelin Does Not Impair Coronary Artery Relaxation Mediated by Nitric Oxide-Induced Activation of BKCa Channels

Apelin Does Not Impair Coronary Artery Relaxation Mediated by Nitric Oxide-Induced Activation of BKCa Channels

Vascular α1A Adrenergic Receptors as a Potential Therapeutic Target for IPAD in Alzheimer’s Disease

Pathophysiological, Cellular, and Molecular Events of the Vascular System in Anaphylaxis

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