Vascular adaptation to pressure and flow involves an intricate interplay of the endothelium, the smooth muscle layer and the extracellular matrix. Shear stress on the endothelium causes vasodilatation, which in turn increases tension in the vascular wall and causes stretch-induced growth (outward remodelling). Reduced endothelial function causes instead increased vascular tone, which leads to inward remodelling of the vascular wall and an increased wall-to-lumen ratio. Vascular smooth muscle cells exposed to physiological levels of stretch grow in a maintained contractile phenotype, in contrast to the proliferative growth seen in vascular lesions and plaque formation. Organ culture of intact blood vessels is a useful technique to study molecular mechanisms of stretch-induced growth with maintained cell-cell and cell-matrix interactions. This technique has been applied to pressurized large and small arteries as well as to veins, revealing basically similar molecular mechanisms but with functional effects dependent on tissue organization and physiological role of the vessel. A convenient model is the rat or mouse portal vein, which has a dominantly longitudinal muscle layer that rapidly hypertrophies in vivo in response to increased portal pressure. Organ culture of portal veins under longitudinal stretch reproduces this growth response (1), and analysis of signal mechanisms shows that stretch causes synthesis of smooth muscle-specific contractile and cytoskeletal proteins, such as SM 22α, calponin, desmin and α-actin, by a sequence of events including biphasic (minutes and hours) phosphorylation of focal adhesion kinase (FAK), early (minutes) phosphorylation of the proliferation-related signal ERK1/2, and late (hours) Rho activation, cofilin phosphorylation and actin polymerisation (2,3). Synthesis of smooth muscle-specific proteins is regulated by the transcription factor serum response factor, in concert with co-factors such as myocardin and myocardin-related transcription factors, which are dependent on the state of actin polymerisation (reviewed in ref. 4). The actin filament stabilising agent jasplakinolide causes increased synthesis of smooth muscle proteins in the mouse portal vein, and also activates the ERK1/2 pathway, whereas effects of stretch on FAK phosphorylation or contractility are abolished (3). This suggests that actin filament dynamics are crucial for vascular remodelling responses. Cholesterol-rich membrane caveolae are important for integrating signal mechanisms in the plasma membrane, and studies in caveolin-1 deficient mice suggest that caveolae are needed for endothelium-dependent relaxation in response to flow, involving Akt phosphorylation and NO production. In contrast, stretch-induced responses in mouse portal vein do not involve Akt phosphorylation and are unaffected in caveolin-1 deficient mice (5). The signal mechanisms regulating contraction and growth responses seem to be integrated partly via the intracellular Ca²⁺ concentration, and evidence suggests that voltage-dependent Ca²⁺ influx via L-type membrane channels elicits smooth muscle differentiation via a Rho kinase dependent mechanism (6). In mouse portal vein, stretch-induced effects on cofilin phosphorylation, regulating actin polymerisation, are attenuated by L-type channel inhibition, correlating with decreased synthesis of smooth muscle marker proteins, while inhibition of Ca²⁺ influx via store-operated channels causes a global decrease in protein synthesis but does not inhibit stretch-induced cofilin phosphorylation or synthesis of smooth muscle-specific proteins. Thus Ca²⁺ exerts a dual influence on the regulation of protein synthesis in vascular smooth muscle. Since phenotype modulation of smooth muscle cells is associated with loss of voltage-dependent channels and gain of store-operated channels, the contractile and synthetic cellular phenotypes may be specifically susceptible to interventions targeting the different modes of Ca²⁺ entry.