University of Tennessee Health Science Center, USA
Salvatore Mancarella, Ph.D. is an Assistant Professor at the University of Tennessee Health Science Center. As a graduate student and postdoc he has devoted his career investigating how calcium fl uctuations control cardiac contraction. Recently he is focusing on understanding how calcium signaling at the sub-membrane space is deciphered into the nucleus to control cell growth and proliferation.
Stromal interaction molecules (STIM1 and STIM2) function as powerful sarcoplasmic (SR) Ca2+ sensors. When the SR Ca2+ content decreases STIM proteins migrate in proximity of the plasma membrane to activate the Orai channels initiating the so called Store Operated Ca2+ Entry (SOCE). A growing body of evidence suggest that the STIM-dependent calcium signaling is required for mediating cell growth and proliferation of cells of the cardiovascular system. We used the Cre-lox technology approach to generate smooth muscle cells (SMC) and cardiac specifi c STIM knock-out SMSTIM1-, sm-STIM2-, and sm-TIM1/STIM2-KO mice, this model allowed us to systematically analyze the physiological role of STIM in smooth muscle cells and the heart. SM-STIM1-KO mice showed a reduced body weight when compared to control mice. Smooth muscle containing organs, such as intestine and aorta harvested from SM-STIM1-KO mice revealed morphological abnormalities when compared with organs harvested from control mice. Vascular reactivity analyzed using wire myography revealed that while depolarizationinduced aortic contraction was unchanged, phenylephrine-mediated contraction was reduced by 26%, and store-dependent contraction was almost eliminated in aortas isolated from SM-STIM1-KO mice. Neointima formation induced by partial carotid artery ligation was suppressed by 54%. Consistently, in vitro PDGF-induced SMC proliferation was also reduced by 79% in STIM1-KO SMC. Defective Ca2+ homeostasis in STIM1 KO smooth muscle cells prevents PDGF-induced NFAT activation in both contractile and proliferating SMCs. In conclusion, our data show that STIM1-regulated Ca2+ homeostasis is required for NFAT-mediated transcriptional control, SMC proliferation, development, and growth during physiological as well as pathophysiological conditions.