Smooth muscle is adapted for contraction but also shows a high degree of plasticity of differentiation and growth in response to environmental influences. Signals carried by a limited number of intracellular second messengers need to be integrated in space and time to fulfill a plethora of specific tasks, and increasing evidence indicates that this is achieved partly by an intricate arrangement of local signal systems organized in microdomains. An example of this is the clustering of receptors and ion channels in cholesterol-rich membrane regions (caveolae or lipid rafts). Part of the contractile response to endothelin-1 (ET-1) in rat tail artery is due to activation of Ca²⁺ inflow via TRPC1 channels, which is sensitive to extraction of membrane cholesterol, correlating with disruption of caveolae (Bergdahl et al. 2003). This suggests clustering of signal molecules into functional units in caveolae. Coupling of caveolae with growth signals is suggested by studies in the isolated rat portal vein, showing that stretch of the vessel wall increases tyrosine phosphorylation of several proteins in a membrane fraction containing the caveolar marker protein caveolin-1 (Zeidan et al. 2003). Stretch also causes activation of ERK1/2 and increased protein synthesis in the portal vein, but these effects were abolished after depletion of cholesterol. Part of the trophic response to stretch may be mediated by endogenous production of angiotensin II and ET-1, and it is interesting that ERK phosphorylation in response to ET-1 but not angiotensin II was found to be inhibited by cholesterol depletion. This demonstrates that local signal pathways responding to the same stimulus (stretch) and mediating the same downstream effect (ERK activation) may differ in their relationship to caveole. The differentiated smooth muscle phenotype is marked by a limited number of contractile and cytoskeletal proteins, whose expression is regulated by serum response factor (SRF; reviewed by Owens et al. 2004). One factor shown to be important for SRF-dependent smooth muscle specific gene expression is the level of actin polymerization, which may influence the translocation of SRF and/or coactivators to the nucleus. In the portal vein, mechanical strain increases actin polymerization by activating its Rho-dependent regulatory pathway, and concomitantly stimulates the synthesis of differentiation marker proteins (Albinsson et al. 2004). Thus stretch of the intact vascular wall activates both an ERK-dependent increase in protein synthesis and a specific Rho-dependent differentiation pattern. At the membrane level, stretch causes biphasic activation of focal adhesion kinase (FAK), where an early peak (15 min) correlates in time with stretch-induced ERK phosphorylation, while a later sustained increase (24 h) correlates with Rho activation. Therefore, the domain organization of signal molecules into caveolae and focal adhesions in the plasma membrane may be essential for transduction of signals regulating contractile activity, growth, and cellular phenotype. Further elucidation of these mechanisms will clarify how environmental conditions influence smooth muscle function, of profound importance for pathophysiological adaptation.