scholarly journals Doxorubicin Impairs Smooth Muscle Cell Contraction: Novel Insights in Vascular Toxicity

2021 ◽  
Vol 22 (23) ◽  
pp. 12812
Author(s):  
Matthias Bosman ◽  
Dustin N. Krüger ◽  
Kasper Favere ◽  
Callan D. Wesley ◽  
Cédric H. G. Neutel ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Arterial Stiffness ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Reactivity ◽  
Transient Receptor Potential ◽  
Ex Vivo ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels

Clinical and animal studies have demonstrated that chemotherapeutic doxorubicin (DOX) increases arterial stiffness, a predictor of cardiovascular risk. Despite consensus about DOX-impaired endothelium-dependent vasodilation as a contributing mechanism, some studies have reported conflicting results on vascular smooth muscle cell (VSMC) function after DOX treatment. The present study aimed to investigate the effects of DOX on VSMC function. To this end, mice received a single injection of 4 mg DOX/kg, or mouse aortic segments were treated ex vivo with 1 μM DOX, followed by vascular reactivity evaluation 16 h later. Phenylephrine (PE)-induced VSMC contraction was decreased after DOX treatment. DOX did not affect the transient PE contraction dependent on Ca2+ release from the sarcoplasmic reticulum (0 mM Ca2+), but it reduced the subsequent tonic phase characterised by Ca2+ influx. These findings were supported by similar angiotensin II and attenuated endothelin-1 contractions. The involvement of voltage-gated Ca2+ channels in DOX-decreased contraction was excluded by using levcromakalim and diltiazem in PE-induced contraction and corroborated by similar K+ and serotonin contractions. Despite the evaluation of multiple blockers of transient receptor potential channels, the exact mechanism for DOX-decreased VSMC contraction remains elusive. Surprisingly, DOX reduced ex vivo but not in vivo arterial stiffness, highlighting the importance of appropriate timing for evaluating arterial stiffness in DOX-treated patients.

PDGF stimulates pulmonary vascular smooth muscle cell proliferation by upregulating TRPC6 expression

2003 ◽  
Vol 284 (2) ◽  
pp. C316-C330 ◽  
Author(s):  
Ying Yu ◽  
Michele Sweeney ◽  
Shen Zhang ◽  
Oleksandr Platoshyn ◽  
Judd Landsberg ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Transient Receptor Potential ◽  
Cyclopiazonic Acid ◽  
Receptor Potential ◽  
Protein Levels ◽  
Resultant Increase ◽  
Transient Receptor

Capacitative Ca2+ entry (CCE) through store-operated Ca2+ (SOC) channels plays an important role in returning Ca2+ to the sarcoplasmic reticulum (SR) and regulating cytosolic free Ca2+concentration ([Ca2+]cyt). A rise in [Ca2+]cyt and sufficient Ca2+ in the SR are required for pulmonary artery smooth muscle cell (PASMC) proliferation. We tested the hypothesis that platelet-derived growth factor (PDGF)-mediated PASMC growth involves upregulation of c-Jun and TRPC6, a transient receptor potential cation channel. In rat PASMC, PDGF (10 ng/ml for 0.5–48 h) phosphorylated signal transducer and activator of transcription (STAT3), increased mRNA and protein levels of c-Jun, and stimulated cell proliferation. PDGF treatment also upregulated TRPC6 expression and augmented CCE, elicited by passive depletion of Ca2+ from the SR using cyclopiazonic acid. Furthermore, overexpression of c-Jun stimulated TRPC6 expression and CCE amplitude in PASMC. Downregulation of TRPC6 using an antisense oligonucleotide specifically for human TRPC6 decreased CCE and inhibited PDGF-mediated PASMC proliferation. These results suggest that PDGF-mediated PASMC proliferation is associated with c-Jun/STAT3-induced upregulation of TRPC6 expression. The resultant increase in CCE raises [Ca2+]cyt, facilitates return of Ca2+ to the SR, and enhances PASMC growth.

Upregulated TRP and enhanced capacitative Ca2+ entry in human pulmonary artery myocytes during proliferation

2001 ◽  
Vol 280 (2) ◽  
pp. H746-H755 ◽  
Author(s):  
Vera A. Golovina ◽  
Oleksandr Platoshyn ◽  
Colleen L. Bailey ◽  
Jian Wang ◽  
Alisa Limsuwan ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Cell Growth ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Transient Receptor Potential ◽  
Mrna Level ◽  
Critical Role ◽  
Receptor Potential ◽  
Intracellular Ca ◽  
Inward Currents

A rise in cytosolic Ca2+ concentration ([Ca2+]cyt) due to Ca2+ release from intracellular Ca2+ stores and Ca2+ influx through plasmalemmal Ca2+ channels plays a critical role in mitogen-mediated cell growth. Depletion of intracellular Ca2+ stores triggers capacitative Ca2+ entry (CCE), a mechanism involved in maintaining Ca2+ influx and refilling intracellular Ca2+ stores. Transient receptor potential ( TRP) genes have been demonstrated to encode the store-operated Ca2+ channels that are activated by Ca2+ store depletion. In this study, we examined whether CCE, activity of store-operated Ca2+ channels, and human TRP1 ( hTRP1) expression are essential in human pulmonary arterial smooth muscle cell (PASMC) proliferation. Chelation of extracellular Ca2+ and depletion of intracellularly stored Ca2+ inhibited PASMC growth in media containing serum and growth factors. Resting [Ca2+]cyt as well as the increases in [Ca2+]cyt due to Ca2+ release and CCE were all significantly greater in proliferating PASMC than in growth-arrested cells. Consistently, whole cell inward currents activated by depletion of intracellular Ca2+ stores and the mRNA level of hTRP1 were much greater in proliferating PASMC than in growth-arrested cells. These results suggest that elevated [Ca2+]cyt and intracellularly stored [Ca2+] play an important role in pulmonary vascular smooth muscle cell growth. CCE, potentially via hTRP1-encoded Ca2+-permeable channels, may be an important mechanism required to maintain the elevated [Ca2+]cyt and stored [Ca2+] in human PASMC during proliferation.

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.

Calcium and TRP Channels in Pulmonary Vascular Smooth Muscle Cell Proliferation

Physiology ◽  
2004 ◽  
Vol 19 (2) ◽  
pp. 44-50 ◽  
Author(s):  
Judd W. Landsberg ◽  
Jason X.-J. Yuan
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Smooth Muscle Cell Proliferation

Ca2+ is a major trigger for pulmonary vasoconstriction and a stimulus for pulmonary vascular smooth muscle cell proliferation. The transient receptor potential cation channels participate in regulating intracellular Ca2+ and thus vascular contractility and cell proliferation. Upregulation of genes encoding these channels is involved in the development of pulmonary hypertension.

scholarly journals Arterial smooth muscle cell PKD2 (TRPP1) channels control systemic blood pressure

2018 ◽  
Author(s):  
Simon Bulley ◽  
Carlos Fernandez-Pena ◽  
Raquibul Hasan ◽  
M. Dennis Leo ◽  
Padmapriya Muralidharan ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Systemic Blood Pressure ◽  
Systemic Blood ◽  
Arterial Smooth Muscle

AbstractSystemic blood pressure is determined, in part, by arterial smooth muscle cells (myocytes). Several Transient Receptor Potential (TRP) channels are proposed to be expressed in arterial myocytes, but it is unclear if these proteins control physiological blood pressure and contribute to hypertension in vivo. We generated the first inducible, smooth muscle-specific knockout for a TRP channel, namely for PKD2 (TRPP1), to investigate arterial myocyte and blood pressure regulation by this protein. Using this model, we show that intravascular pressure and α1-receptors activate PKD2 channels in arterial myocytes of different systemic organs. PKD2 channel activation in arterial myocytes leads to an inward Na+ current, membrane depolarization and vasoconstriction. Inducible, smooth muscle cell-specific PKD2 knockout lowers both physiological blood pressure and hypertension and prevents pathological arterial remodeling during hypertension. In summary, we show for the first time that arterial myocyte PKD2 channels control systemic blood pressure and targeting reduces high blood pressure.

scholarly journals Smooth muscle cell transient receptor potential polycystin-2 (TRPP2) channels contribute to the myogenic response in cerebral arteries

2013 ◽  
Vol 591 (20) ◽  
pp. 5031-5046 ◽  
Author(s):  
Damodaran Narayanan ◽  
Simon Bulley ◽  
M. Dennis Leo ◽  
Sarah K. Burris ◽  
Kyle S. Gabrick ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Transient Receptor Potential ◽  
Cerebral Arteries ◽  
Receptor Potential ◽  
Myogenic Response ◽  
Transient Receptor
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