Calcium (Ca 2+ ) is a highly versatile second messenger that controls vascular smooth muscle cell (VSMC) contraction, proliferation, and migration. By means of Ca 2+ permeable channels, Ca 2+ pumps and channels conducting other ions such as potassium and chloride, VSMC keep intracellular Ca 2+ levels under tight control. In healthy quiescent contractile VSMC, two important components of the Ca 2+ signaling pathways that regulate VSMC contraction are the plasma membrane voltageoperated Ca 2+ channel of the high voltage-activated type (L-type) and the sarcoplasmic reticulum Ca 2+ release channel, Ryanodine Receptor (RyR). Injury to the vessel wall is accompanied by VSMC phenotype switch from a contractile quiescent to a proliferative motile phenotype (synthetic phenotype) and by alteration of many components of VSMC Ca 2+ signaling pathways. Specifically, this switch that culminates in a VSMC phenotype reminiscent of a non-excitable cell is characterized by loss of L-type channels expression and increased expression of the low voltage-activated (T-type) Ca 2+ channels and the canonical transient receptor potential (TRPC) channels. The expression levels of intracellular Ca 2+ release channels, pumps and Ca 2+ -activated proteins are also altered: the proliferative VSMC lose the RyR3 and the sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase isoform 2a pump and reciprocally regulate isoforms of the ca 2+ /calmodulin-dependent protein kinase II. This review focuses on the changes in expression of Ca 2+ signaling proteins associated with VSMC proliferation both in vitro and in vivo. The physiological implications of the altered expression of these Ca 2+ signaling molecules, their contribution to VSMC dysfunction during vascular disease and their potential as targets for drug therapy will be discussed.

House SJ, Ginnan RG, Armstrong SE, Singer HA. Calcium/ calmodulin-dependent protein kinase II-␦ isoform regulation of vascular smooth muscle cell proliferation.

Objective-The purpose of this study was to test the function of the calcium/calmodulin-dependent protein kinase II ␦ 2 isoform (CaMKII␦ 2 ) in regulating vascular smooth muscle (VSM) cell proliferation and migration in response to vascular injury. Methods and Results-CaMKII isoform content was assessed in rat carotid arteries after balloon angioplasty-induced injury by Western blotting with isoform specific antibodies. Within 3 days after injury, a significant increase in CaMKII␦ 2 and decrease in CaMKII␥ isoform content was observed in both medial smooth muscle and adventitial fibroblasts. Neointimal VSM cells expressed primarily the ␦ 2 isoform. Incubation of the injured vessel with adenovirus encoding siRNA targeting CaMKII␦ isoforms prevented upregulation of the ␦ 2 isoform in the media and adventitia; inhibited cell proliferation assessed by PCNA expression in both layers and markedly inhibited neointima formation and adventitial thickening. Conclusions-CaMKII␦ 2 is specifically induced in VSM and adventitial fibroblasts during the response of an artery to injury and is a positive regulator of proliferation and migration in the vessel wall contributing to neointima formation and vascular remodeling. This provides a potential mechanism for Ca 2ϩ -dependent regulation of VSM and myofibroblast proliferation and migration in response to vascular injury or disease. Key Words: CaMKII Ⅲ VSM proliferation Ⅲ vascular injury Ⅲ restenosis Ⅲ neointima V ascular smooth muscle (VSM) cell phenotype modulation and proliferation is a hallmark of disease or injuryinduced remodeling of the vascular wall and is regulated by diverse environmental stimuli including peptide growth factors, extracellular matrix, vasoactive factors, mechanical forces, and oxidative stress. 1 Identification of intracellular signaling pathways that integrate this information to regulate VSM cell phenotype and proliferative responses is an active field of research. Ca 2ϩ signals can coordinate multiple functions in VSM including contractile activity, metabolism, and gene transcription. 2 There is evidence to suggest that different sources or spatiotemporal patterns of Ca 2ϩ signals may be processed to result in specific patterns of gene expression. 3 Similar "excitation-transcription" coupling mechanisms have been proposed in neurons and striated muscle. 4 Of particular interest with respect to vascular disease mechanisms is recent evidence indicating that injury-induced changes in VSM Ca 2ϩ dynamics may contribute to development of a migratory/proliferative phenotype associated with neoinitma formation. 3,5 We have investigated the multifunctional serine/threonine kinase Ca 2ϩ /calmodulin-dependent protein kinase II (CaMKII) as a mediator of Ca 2ϩ signals regulating VSM cell function. A large number of splice variants from 4 differentially expressed CaMKII genes (␣, ␤, ␥, and ␦) have been identified, 6 and there is increasing evidence that isoformspecific structural variations can affect subcellular targeting and function of the kinase. 7 Differenti...

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Conclusion: Male victims of copperhead snake envenomation demonstrate slightly better recovery than females during the first 14 days after treatment, but response to Fab antivenom overall is similar across all subgroups studied.