scholarly journals Disruption of Pressure-Induced Ca 2+ Spark Vasoregulation of Resistance Arteries, Rather Than Endothelial Dysfunction, Underlies Obesity-Related Hypertension

Hypertension ◽  
2020 ◽  
Vol 75 (2) ◽  
pp. 539-548 ◽  
Author(s):  
Adam S. Greenstein ◽  
Sharifah Zamiah Abdul Syed Kadir ◽  
Viktoria Csato ◽  
Sarah A. Sugden ◽  
Rachael A. Baylie ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Signaling Pathways ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Intraluminal Pressure ◽  
Pharmacological Intervention ◽  
Resistance Arteries ◽  
High Fat ◽  
Transient Receptor

Obesity-related hypertension is one of the world’s leading causes of death and yet little is understood as to how it develops. As a result, effective targeted therapies are lacking and pharmacological treatment is unfocused. To investigate underlying microvascular mechanisms, we studied small artery dysfunction in a high fat–fed mouse model of obesity. Pressure-induced constriction and responses to endothelial and vascular smooth muscle agonists were studied using myography; the corresponding intracellular Ca 2+ signaling pathways were examined using confocal microscopy. Principally, we observed that the enhanced basal tone of mesenteric resistance arteries was due to failure of intraluminal pressure-induced Ca 2+ spark activation of the large conductance Ca 2+ activated K + potassium channel (BK) within vascular smooth muscle cells. Specifically, the uncoupling site of this mechanotransduction pathway was at the sarcoplasmic reticulum, distal to intraluminal pressure-induced oxidation of Protein Kinase G. In contrast, the vasodilatory function of the endothelium and the underlying endothelial IP-3 and TRPV4 (vanilloid 4 transient receptor potential ion channel) Ca 2+ signaling pathways were not affected by the high-fat diet or the elevated blood pressure. There were no structural alterations of the arterial wall. Our work emphasizes the importance of the intricate cellular pathway by which intraluminal pressure maintains Ca 2+ spark vasoregulation in the origin of obesity-related hypertension and suggests previously unsuspected avenues for pharmacological intervention.

scholarly journals Increased arterial smooth muscle Ca2+ signaling, vasoconstriction, and myogenic reactivity in Milan hypertensive rats

2012 ◽  
Vol 302 (3) ◽  
pp. H611-H620 ◽  
Author(s):  
Cristina I. Linde ◽  
Eiji Karashima ◽  
Hema Raina ◽  
Alessandra Zulian ◽  
Withrow G. Wier ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Transient Receptor Potential ◽  
Genetic Model ◽  
Receptor Potential ◽  
Whole Body ◽  
Resistance Arteries ◽  
Arterial Smooth Muscle ◽  
Functional Changes ◽  
Arterial Constriction ◽  
Transient Receptor

The Milan hypertensive strain (MHS) rats are a genetic model of hypertension with adducin gene polymorphisms linked to enhanced renal tubular Na+ reabsorption. Recently we demonstrated that Ca2+ signaling is augmented in freshly isolated mesenteric artery myocytes from MHS rats. This is associated with greatly enhanced expression of Na+/Ca2+ exchanger-1 (NCX1), C-type transient receptor potential (TRPC6) protein, and sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2) compared with arteries from Milan normotensive strain (MNS) rats. Here, we test the hypothesis that the enhanced Ca2+ signaling in MHS arterial smooth muscle is directly reflected in augmented vasoconstriction [myogenic and phenylephrine (PE)-evoked responses] in isolated mesenteric small arteries. Systolic blood pressure was higher in MHS (145 ± 1 mmHg) than in MNS (112 ± 1 mmHg; P < 0.001; n = 16 each) rats. Pressurized mesenteric resistance arteries from MHS rats had significantly augmented myogenic tone and reactivity and enhanced constriction to low-dose (1–100 nM) PE. Isolated MHS arterial myocytes exhibited approximately twofold increased peak Ca2+ signals in response to 5 μM PE or ATP in the absence and presence of extracellular Ca2+. These augmented responses are consistent with increased vasoconstrictor-evoked sarcoplasmic reticulum (SR) Ca2+ release and increased Ca2+ entry, respectively. The increased SR Ca2+ release correlates with a doubling of inositol 1,4,5-trisphosphate receptor type 1 and tripling of SERCA2 expression. Pressurized MHS arteries also exhibited a ∼70% increase in 100 nM ouabain-induced vasoconstriction compared with MNS arteries. These functional alterations reveal that, in a genetic model of hypertension linked to renal dysfunction, multiple mechanisms within the arterial myocytes contribute to enhanced Ca2+ signaling and myogenic and vasoconstrictor-induced arterial constriction. MHS rats have elevated plasma levels of endogenous ouabain, which may initiate the protein upregulation and enhanced Ca2+ signaling. These molecular and functional changes provide a mechanism for the increased peripheral vascular resistance (whole body autoregulation) that underlies the sustained hypertension.

scholarly journals Epidermal growth factor signaling through transient receptor potential melastatin 7 cation channel regulates vascular smooth muscle cell function

2020 ◽  
Vol 134 (15) ◽  
pp. 2019-2035 ◽  
Author(s):  
Zhi-Guo Zou ◽  
Francisco J. Rios ◽  
Karla B. Neves ◽  
Rheure Alves-Lopes ◽  
Jiayue Ling ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Epidermal Growth ◽  
Transient Receptor

Abstract Objective: Transient receptor potential (TRP) melastatin 7 (TRPM7) cation channel, a dual-function ion channel/protein kinase, regulates vascular smooth muscle cell (VSMC) Mg2+ homeostasis and mitogenic signaling. Mechanisms regulating vascular growth effects of TRPM7 are unclear, but epidermal growth factor (EGF) may be important because it is a magnesiotropic hormone involved in cellular Mg2+ regulation and VSMC proliferation. Here we sought to determine whether TRPM7 is a downstream target of EGF in VSMCs and if EGF receptor (EGFR) through TRPM7 influences VSMC function. Approach and results: Studies were performed in primary culture VSMCs from rats and humans and vascular tissue from mice deficient in TRPM7 (TRPM7+/Δkinase and TRPM7R/R). EGF increased expression and phosphorylation of TRPM7 and stimulated Mg2+ influx in VSMCs, responses that were attenuated by gefitinib (EGFR inhibitor) and NS8593 (TRPM7 inhibitor). Co-immunoprecipitation (IP) studies, proximity ligation assay (PLA) and live-cell imaging demonstrated interaction of EGFR and TRPM7, which was enhanced by EGF. PP2 (c-Src inhibitor) decreased EGF-induced TRPM7 activation and prevented EGFR–TRPM7 association. EGF-stimulated migration and proliferation of VSMCs were inhibited by gefitinib, PP2, NS8593 and PD98059 (ERK1/2 inhibitor). Phosphorylation of EGFR and ERK1/2 was reduced in VSMCs from TRPM7+/Δkinase mice, which exhibited reduced aortic wall thickness and decreased expression of PCNA and Notch 3, findings recapitulated in TRPM7R/R mice. Conclusions: We show that EGFR directly interacts with TRPM7 through c-Src-dependent processes. Functionally these phenomena regulate [Mg2+]i homeostasis, ERK1/2 signaling and VSMC function. Our findings define a novel signaling cascade linking EGF/EGFR and TRPM7, important in vascular homeostasis.

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