The dynamic regulation of blood vessel caliber

The blood vessel. Endothelial cells (green ovals) are exposed to a variety of stimuli, including mechanical forces of pressure and flow (shear stress), drugs, hormones, and toxins. Endothelial cells transduce these stimuli and respond by sending messages to smooth muscle cells (red ovals) , which leads to responses such as contraction, relaxation, proliferation, migration, or synthesis of proteins.

Myosin (yellow) is a motor protein that, when activated, leads to formation of cross-bridges with actin and sliding of actin thin filaments to a more shortened configuration (thick filament regulation). Actin (thin yellow line) is associated with a variety of proteins, including tropomyosin, caldesmon, calponin, and small heat shock proteins, which may be important in maintenance of force (thin filament regulation). We propose a model for maintenance of force in smooth muscle (tethering domain model) in which phosphorylated HSP27 (P-HSP27; orange oval) tethers actin with a specific but unknown domain protein (green squares) . During relaxation, phosphorylated HSP20 (P-HSP20, purple triangle) directly interacts with phosphorylated HSP27, thus destabilizing interaction of actin with domain protein.

Thick filament regulation of smooth muscle contraction. Increases in calcium (Ca ²⁺) activate myosin light chain kinase (MLCK), which phosphorylates regulatory light chains (MLC) on the myosin motor molecule. Regulatory light chains are dephosphorylated by myosin light chain phosphatase (MLC Ppase) , which has recently been shown to be inhibited by Rho-activated kinase (ROK) . Thick filament regulation of smooth muscle contraction assumes that force is dependent on the phosphorylation state of regulatory myosin light chains.

Relationship between calcium concentrations, myosin light chain phosphorylation, and force development in vascular smooth muscle contraction. Stimulation of vascular smooth muscles with a contractile agonist (A) leads to rapid increases in calcium concentrations (dotted line) followed by increases in phosphorylation of regulatory myosin light chains (dashed lines) and development of force (solid line) . During the sustained phase of muscle contraction, calcium concentrations and myosin light chain phosphorylation return to near basal levels.