Targeted STIM deletion impairs calcium homeostasis, NFAT activation, and growth of smooth muscle

The Ca²⁺-sensing stromal interaction molecule (STIM) proteins are crucial Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ store-refilling rate in STIM1-KO SMCs was substantially reduced, and sustained PDGF-induced Ca²⁺ entry was abolished. This defective Ca²⁺ homeostasis prevents PDGF-induced NFAT activation in both contractile and proliferating SMCs. We conclude that STIM1-regulated Ca²⁺ homeostasis is crucial for NFAT-mediated transcriptional control required for induction of SMC proliferation, development, and growth responses to injury.