ABSTRACT
The Rho-kinase (ROK)-mediated Ca2+-sensitization of vascular smooth muscles (VSM) contraction contributes to vasospasm, a major cause of acute-onset sudden death induced by vascular diseases such as ischemic heart and brain diseases. As an upstream signaling molecule of such abnormal vascular contraction leading to vasospasm, we previously identified sphingosylphosphorylcho-line (SPC), which induced the Ca2+-sensitization of VSM contraction in vitro and in vivo through the sequential activation of Fyn (a Src family tyrosine kinase) and ROK. The marked elevation
of SPC level was also observed in the vasospastic patients, indicating that SPC is a causal factor of the Ca2+-sensitization leading to vasospasm. Surprisingly we found the significant linkage between the extent of SPC-induced contraction and serum total cholesterol level in both human and rabbits. This review covers the current knowledge of the mechanisms by which SPC induces Ca2+-sensitization leading to vasospasm and the roles of cholesterol and its enriched membrane microdomains, membrane lipid rafts. 13.1 IntroductionVasospasm, such as coronary artery vasospasm and cerebral vasospasm, is one of causes for sudden death or a major lethal complication for patients after subarachnoid hemorrhage (SAH). This vasospasm means that a sustained abnormal contraction from coronary artery or cerebral vascular artery. Vascular smooth muscles (VSM) have two types of contraction, Ca2+-dependent contraction and Ca2+-independent contraction, i.e., Ca2+-sensitization (Ganitkevich et al., 2002; Gao et al., 2013; Kureishi et al., 1997; Mizuno et al., 2008; Moreland et al., 1991; Somlyo and Somlyo, 2003). Ca2+-dependent contraction plays an important role in the maintenance of physiologic blood pressure. This process is regulated by the Ca2+/calmodulin-myosin light chain kinase (MLCK)-mediated pathway. When concentration of cytoplasmic Ca2+ increases, this increased Ca2+ binds to calmodulin and Ca2+/calmodulin complex activates MLCK. The activated MLCK phosphorylates myosin light chain (MLC) and then produces the contraction (Gao et al., 2013; Mizuno et al., 2008; Moreland et al., 1991). On the other hand, Ca2+-independent contraction, i.e., Ca2+-sensitization induces abnormal contraction of VSM through a mechanism that is independent of Ca2+/calmodulin-MLCK-mediated pathway (Gailly et al., 1997; Jensen et al., 1996; Kureishi et al., 1997; Kobayashi et al., 1991). It has been proposed a major cause of cardio-cerebral-vascular diseases, such as coronary artery vasospasm and cerebral vasospasm. In this review, we focused on and elaborated the mechanisms of Ca2+-sensitization leading to vasospasm and the roles of cholesterol and its enriched membrane microdomains, membrane lipid rafts.
