Stimulation of vascular smooth muscle cell proliferation by stiff matrix via the IKCa channel‐dependent Ca2+ signaling
- 1 March 2021
- journal article
- research article
- Published by Wiley in Journal of Cellular Physiology
- Vol. 236 (10), 6897-6906
- https://doi.org/10.1002/jcp.30349
Abstract
Vascular stiffening, an early and common characteristic of cardiovascular diseases (CVDs), stimulates vascular smooth muscle cell (VSMC) proliferation which reciprocally accelerates the progression of CVDs. However, the mechanisms by which extracellular matrix stiffness accompanying vascular stiffening regulates VSMC proliferation remain largely unknown. In the present study, we examined the role of the intermediate‐conductance Ca2+‐activated K+ (IKCa) channel in the matrix stiffness regulation of VSMC proliferation by growing A7r5 cells on soft and stiff polydimethylsiloxane substrates with stiffness close to these of arteries under physiological and pathological conditions, respectively. Stiff substrates stimulated cell proliferation and upregulated the expression of the IKCa channel. Stiff substrate‐induced cell proliferation was suppressed by pharmacological inhibition using TRAM34, an IKCa channel blocker, or genetic depletion of the IKCa channel. In addition, stiff substrate‐induced cell proliferation was also suppressed by reducing extracellular Ca2+ concentration using EGTA or intracellular Ca2+ concentration using BAPTA‐AM. Moreover, stiff substrate induced activation of extracellular signal‐regulated kinases (ERKs), which was inhibited by treatment with TRAM34 or BAPTA‐AM. Stiff substrate‐induced cell proliferation was suppressed by treatment with PD98059, an ERK inhibitor. Taken together, these results show that substrates with pathologically relevant stiffness upregulate the IKCa channel expression to enhance intracellular Ca2+ signaling and subsequent activation of the ERK signal pathway to drive cell proliferation. These findings provide a novel mechanism by which vascular stiffening regulates VSMC function.Funding Information
- China Scholarship Council (201906025008)
- National Natural Science Foundation of China (11421202, 11827803, 11872010, U20A20390)
This publication has 42 references indexed in Scilit:
- Calcium Channels in Vascular Smooth MusclePublished by Elsevier BV ,2016
- Functional cooperation between KCa3.1 and TRPC1 channels in human breast cancer: Role in cell proliferation and patient prognosisOncotarget, 2016
- The Intermediate Conductance Calcium-activated Potassium Channel KCa3.1 Regulates Vascular Smooth Muscle Cell Proliferation via Controlling Calcium-dependent SignalingOnline Journal of Public Health Informatics, 2013
- Role of arterial stiffness in cardiovascular diseaseJRSM Cardiovascular Disease, 2012
- Aortic StiffnessJournal of the American College of Cardiology, 2011
- Effect of substrate stiffness and PDGF on the behavior of vascular smooth muscle cells: Implications for atherosclerosisJournal of Cellular Physiology, 2010
- Accelerated Ca2+entry by membrane hyperpolarization due to Ca2+-activated K+channel activation in response to histamine in chondrocytesAmerican Journal of Physiology-Cell Physiology, 2010
- TRPC channels in smooth muscle cellsFrontiers in Bioscience-Landmark, 2010
- Histamine hyperpolarizes human glioblastoma cells by activating the intermediate-conductance Ca2+-activated K+ channelAmerican Journal of Physiology-Cell Physiology, 2009
- Shear stress-induced up-regulation of the intermediate-conductance Ca(2+)-activated K(+) channel in human endothelium.Cardiovascular Research, 2003