title: Targeted STIM deletion impairs calcium homeostasis, NFAT activation, and growth of smooth muscle.
abstract: The Ca(2+)-sensing stromal interaction molecule (STIM) proteins are crucial Ca(2+) signal coordinators. Cre-lox technology was used to generate smooth muscle (sm)-targeted STIM1-, STIM2-, and double STIM1/STIM2-knockout (KO) mouse models, which reveal the essential role of STIM proteins in Ca(2+) homeostasis and their crucial role in controlling function, growth, and development of smooth muscle cells (SMCs). Compared to Cre(+/-) littermates, sm-STIM1-KO mice showed high mortality (50% by 30 d) and reduced bodyweight. While sm-STIM2-KO was without detectable phenotype, the STIM1/STIM double-KO was perinatally lethal, revealing an essential role of STIM1 partially rescued by STIM2. Vascular and intestinal smooth muscle tissues from sm-STIM1-KO mice developed abnormally with distended, thinned morphology. While depolarization-induced aortic contraction was unchanged in sm-STIM1-KO mice, α1-adrenergic-mediated contraction was 26% reduced, and store-dependent contraction almost eliminated. Neointimal formation induced by carotid artery ligation was suppressed by 54%, and in vitro PDGF-induced proliferation was greatly reduced (79%) in sm-STIM1-KO. Notably, the Ca(2+) store-refilling rate in STIM1-KO SMCs was substantially reduced, and sustained PDGF-induced Ca(2+) entry was abolished. This defective Ca(2+) homeostasis prevents PDGF-induced NFAT activation in both contractile and proliferating SMCs. We conclude that STIM1-regulated Ca(2+) homeostasis is crucial for NFAT-mediated transcriptional control required for induction of SMC proliferation, development, and growth responses to injury.-Mancarella, S., Potireddy, S., Wang, Y., Gao, H., Gandhirajan, K., Autieri, M., Scalia, R., Cheng, Z., Wang, H., Madesh, M., Houser, S. R., Gill, D. L. Targeted STIM deletion impairs calcium homeostasis, NFAT activation, and growth of smooth muscle.
authors.affiliation: Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA. mancas@temple.edu
authors.forename: Salvatore
authors.initials: S
authors.lastname: Mancarella
authors.forename: Santhi
authors.initials: S
authors.lastname: Potireddy
authors.forename: Youjun
authors.initials: Y
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Gao
authors.forename: Rajesh Kumar
authors.initials: RK
authors.lastname: Gandhirajan
authors.forename: Michael
authors.initials: M
authors.lastname: Autieri
authors.forename: Rosario
authors.initials: R
authors.lastname: Scalia
authors.forename: Zhongjian
authors.initials: Z
authors.lastname: Cheng
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Muniswamy
authors.initials: M
authors.lastname: Madesh
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
authors.forename: Donald L
authors.initials: DL
authors.lastname: Gill
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels; D049109:Cell Proliferation; D017353:Gene Deletion; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D058426:Neointima / Q000235:genetics / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
chemical_list: D015220:Calcium Channels; D008562:Membrane Glycoproteins; D050778:NFATC Transcription Factors; D010982:Platelet-Derived Growth Factor; C100757:Stim1 protein, mouse; C525024:Stim2 protein, mouse; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; D002118:Calcium