INTEGRATION OF SIGNAL PATHWAYS FOR STRETCH-DEPENDENT GROWTH AND DIFFERENTIATION IN VASCULAR SMOOTH MUSCLE.

• Vascular smooth muscle phenotype is regulated by environmental factors, such as mechanical forces, which exert effects on signaling to differentiation and growth. We used the mouse portal vein in organ culture to investigate stretch-dependent activation of Akt, extracellular regulated protein kinase (ERK) and focal adhesion kinase (FAK), which have been suggested to be involved in the regulation of stretch-dependent protein synthesis. The role of actin polymerization in these signaling events was examined using the actin stabilizing agent jasplakinolide. Stretch caused a biphasic activation of FAK at 5-15 minutes and 24-72 hours, which may reflect first a direct phosphorylation of preexisting focal adhesions followed by a rearrangement of focal adhesions to accommodate for the increased mechanical load. Phosphorylation of ERK was increased by acute stretch but then decreased, and Akt did not have a distinct peak in stretch-induced phosphorylation. Inhibition of ERK, phosphatidylinositol 3-kinase (PI3K) or mammalian target of rapamycin (mTOR) reduced global but not contractile protein synthesis with maintained stretch sensitivity. Stabilization of actin filaments with jasplakinolide, in unstretched portal veins, resulted in increased ERK phosphorylation and global protein synthesis as well as synthesis of contractile proteins. In contrast, stretch during culture with jasplakinolide did not affect FAK phosphorylation or contractility. Therefore, remodeling of smooth muscle cells to adapt to stretch requires a dynamic cytoskeleton. Key words: actin polymerization, MAP kinase, PI3 kinase, focal adhesion kinase, protein synthesis.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Physiology (hsv//eng)

Nyckelord

phosphatidylinositol 3-kinase

protein synthesis

actin polymerization

mitogen-activated protein kinase

focal adhesion kinase

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