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1 Pharmacology, University of Vermont, Burlington, VT, USA
* To whom correspondence should be addressed. E-mail: keith.wilkerson{at}uvm.edu.
Vascular damage signals smooth muscle cells to proliferate, often exacerbating existent pathologies. Although the role of changes in global Ca2+ in vascular smooth muscle (VSM) cell dedifferentiation has been studied, the role that specific Ca2+ signals play in determining VSM phenotype remains relatively unexplored. Prior work with cultured VSM suggests that inositol-1,4,5-trisphosphate receptor (IP3R) expression and sarcoplasmic reticulum (SR) Ca2+ release may be linked to VSM cell proliferation in native tissue. Thus, we hypothesized that SR Ca2+ release through IP3Rs in the form of discrete transient signals is necessary for VSM proliferation. To investigate this, we designed an organ culture system using mouse cerebral arteries that permitted examination of Ca2+ dynamics in native tissue. Explanted arteries were cultured in normal media with 10% FBS and the appearance of individual VSM cells migrating from the explanted arteries (outgrowth cells) was tracked daily. Initial exposure to 10% FBS increased Ca2+ waves in myocytes in the arteries, which were blocked by the IP3R antagonist, 2-aminethoxydiphenylborate (2-APB). Inhibition of IP3R opening (via 100 µM 2-APB, 10 µM xestospongin C or 25 µM U73122) dramatically reduced outgrowth cell number in comparison to untreated or ryanodine-treated (10 µM) arteries. Consistent with this, 2-APB treatment inhibited cell proliferation, as measured by reduced PCNA immunostaining within 48 hours of culture, but did not inhibit cell migration. These results indicate that activation of IP3R Ca2+ release is required for VSM cell proliferation in these arteries.
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