Mechanisms of vascular smooth muscle cell migration.
Smooth muscle cell migration occurs during vascular development, in response to vascular injury, and during atherogenesis. Many proximal signals and signal transduction pathways activated during migration have been identified, as well as components of the cellular machinery that affect cell movement. In this review, a summary of promigratory and antimigratory molecules belonging to diverse chemical and functional families is presented, along with a summary of key signaling events mediating migration. Extracellular molecules that modulate migration include small biogenic amines, peptide growth factors, cytokines, extracellular matrix components, and drugs used in cardiovascular medicine. Promigratory stimuli activate signal transduction cascades that trigger remodeling of the cytoskeleton, change the adhesiveness of the cell to the matrix, and activate motor proteins. This review focuses on the signaling pathways and effector proteins regulated by promigratory and antimigratory molecules. Prominent pathways include phosphatidylinositol 3-kinases, calcium-dependent protein kinases, Rho-activated protein kinase, p21-activated protein kinases, LIM kinase, and mitogen-activated protein kinases. Important downstream targets include myosin II motors, actin capping and severing proteins, formins, profilin, cofilin, and the actin-related protein-2/3 complex. Actin filament remodeling, focal contact remodeling, and molecular motors are coordinated to cause cells to migrate along gradients of chemical cues, matrix adhesiveness, or matrix stiffness. The result is recruitment of cells to areas where the vessel wall is being remodeled. Vessel wall remodeling can be antagonized by common cardiovascular drugs that act in part by inhibiting vascular smooth muscle cell migration. Several therapeutically important drugs act by inhibiting cell cycle progression, which may reduce the population of migrating cells.
Gerthoffer
William T
WT
Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA. wtg@med.unr.edu
D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology