Upregulation of TRPM7 channels by angiotensin II triggers phenotypic switching of vascular smooth muscle cells of ascending aorta.
BACKGROUND
Angiotensin II (Ang II) has pleiotropic effects on vascular smooth muscle cells (VSMCs). It has been demonstrated to promote the proliferative phenotype of VSMCs in mouse ascending aorta, but the underlying mechanisms remain incompletely understood.


OBJECTIVE
The present study was designed to explore whether the Ca(2+)-permeable transient receptor potential melastatin 7 (TRPM7) channel is involved in Ang II-induced phenotype switching of ascending aortic VSMCs and to dissect the molecular mechanisms by which TRPM7 modulates VSMC phenotype.


RESULTS
As revealed by current recording, Ang II infusion increased TRPM7 whole-cell currents in ascending aortic VSMCs. The increase in TRPM7 currents was found to result from enhanced expression of TRPM7 protein rather than elevated single-channel activity (open probability and slope conductance) and/or reduced Mg(2+)-mediated channel block. Mechanistically, Ang II elevated TRPM7 expression via Ang II type 1 receptor-mediated ERK1/2 signaling. As indicated by the expression levels of VSMC differentiation marker genes, phenotypic switching of ascending aorta occurred during Ang II infusion. Meanwhile, ERK1/2-Elk-1 signaling pathway known to suppress VSMC differentiation was activated in Ang II-infused ascending aorta. Knockdown of TRPM7 with small interfering RNA established a causative role of TRPM7 in Ang II-induced phenotypic change and promotion of cell proliferation. Moreover, TRPM7 was shown to be required for Pyk2-ERK1/2-Elk-1 pathway activation by Ang II, which potentiated TRPM7 channel function and thus activated the Ca(2+)-sensitive kinase Pyk2. Finally, TRPM7 knockdown attenuated Ang II-induced displacement of myocardin from SM22 promoter, but the effects could be reversed by expression of constitutively active c-Src.


CONCLUSIONS
Our data establish that upregulation of TRPM7 channels by Ang II contributes to the development of the proliferative phenotype of ascending aortic VSMCs, and TRPM7 channel suppresses VSMC gene expression via Ca(2+) influx-mediated activation of Pyk2-ERK1/2-Elk-1 pathway.
Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, 74 Zhongshan 2nd Rd, Guangzhou, China 510080. zzhang510@gmail.com
Zheng
Z
Zhang
Mi
M
Wang
Xiao-Han
XH
Fan
Jing-Hui
JH
Chen
Yong-Yuan
YY
Guan
Yong-Bo
YB
Tang
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D051418:Focal Adhesion Kinase 2 / Q000187:drug effects / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D050053:TRPM Cation Channels / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology; D050807:ets-Domain Protein Elk-1 / Q000187:drug effects / Q000502:physiology
C494113:Elk1 protein, mouse; D050053:TRPM Cation Channels; D050807:ets-Domain Protein Elk-1; D000804:Angiotensin II; C421903:Trpm7 protein, mouse; D051418:Focal Adhesion Kinase 2; C496053:Ptk2b protein, mouse