Calcium/Calmodulin Activated Kinases in Smooth Muscle

Albany Medical College, Albany NY

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Abstract

PROJECT SUMMARY Migration and proliferation of vascular smooth muscle (VSM) cells occurs during development, wound healing, angiogenesis, and contributes to the progression of vascular disease. Ca2+ signals are known to regulate motility, although this knowledge has not been well integrated into molecular models, due in part to lack of insight into effector mechanisms and targets. Ongoing work funded by this grant has focused on the structure and function of one major Ca2+ signal effector, namely the ubiquitous multifunctional serine/threonine protein kinase, Ca2+/calmodulin-dependent protein kinase II (CaMKII). Given our published and preliminary progress, we are poised to test specific mechanisms by which CaMKII regulates VSM cell motility (Aims 1,2). VSM cell migration and proliferation are properties of ?synthetic phenotype? cells that have not acquired, or have lost, differentiated contractile protein markers and function. Mechanisms controlling VSM cell phenotypic modulation between differentiated contractile and proliferative/migratory states are of considerable interest and clinical importance, but are incompletely understood. One emerging concept, consistent with results from the past funding period, is that disease- or injury-induced changes in Ca2+ signaling mechanisms and dynamics contributes to development of the migratory/proliferative VSM phenotype promoting vascular wall remodeling. The objectives of Aims 3,4 are to test potential mechanisms by which specific CaMKII isozymes regulate VSM synthetic cell phenotype and function. These objectives will be met by pursuing four aims: 1.) We will test the hypothesis that activation of CaMKII[unreadable]2 promotes VSM cell polarization and modulates leading edge dynamics necessary for directed cell migration. Molecular approaches will be used to manipulate CaMKII activity allowing us to decipher catalytic vs. potential scaffolding functions of the kinase, as well as isoform specific functions. 2.) We will test the hypothesis that CaMKII regulates leading edge focal adhesion dynamics, 3.) We will evaluate the function of specific CaMKII isozymes as regulators of the transcriptional repressor REST/NRSF expression and activity in VSM in vitro and in vivo in response to vascular injury, and 4.) We will evaluate the function of specific CaMKII isozymes as regulators of HDAC4 activity in VSM, providing a potential mechanism for VSM gene regulation and promotion of the synthetic phenotype. By elucidating the functional consequences of CaMKII isoform modulation in response to vascular injury, the results of these studies are expected to provide fresh insights into mechanisms underlying phenotypic modulation of VSM cells and mechanism(s) by which Ca2+ signals and a prominent Ca2+-dependent multifunctional protein kinase modulates VSM cell function and contributes to vascular disease.