Cyclic Strain Stress-induced Mitogen-activated Protein Kinase (MAPK) Phosphatase 1 Expression in Vascular Smooth Muscle Cells Is Regulated by Ras/Rac-MAPK Pathways

Abstract

Recently, we demonstrated that mechanical stress results in rapid phosphorylation or activation of plateletderived growth factor receptors in vascular smooth muscle cells ( Intracellular signaling stimulated by growth factors, cytokines, osmotic shock, and stress involves the initiation of one or more phosphorylation cascades leading to the rapid and reversible activation of mitogen-activated protein kinases (MAPKs), 1 a family of ubiquitous and well characterized serine/threonine kinases thought to play a critical role in regulating cellular events required for cell growth, differentiation, and apoptosis (1-3). Three major subfamilies of MAPKs have been identified, including the extracellular signal-regulated kinases (ERKs), c-Jun NH 2 -terminal protein kinases (JNKs) or stress-activated protein kinases (SAPKs), and p38 MAPKs (1-3). They are strongly activated in the arterial wall in response to angioplasty (4 -7), hypertension (8), and hypercholesterolemia, 2 which are risk factors for vascular diseases.MAPK phosphatase-1 (MKP-1) has dual catalytic activity toward phosphotyrosine-and phosphothreonine-containing proteins and is known to inactivate ERKs and possibly JNKs/ SAPKs (9 -12), which play an important role in the regulation of mitogenesis. MKP-1, regulated at the transcriptional level, is induced in vascular smooth muscle cells (VSMCs) by growth factors (13), oxidative stress (14), arachidonic acid (15), and 12-O-tetradecanoylphorbol-13-acetate (16). Although MKP-1 has been implicated in a feedback loop that inactivates MAPKs after stimulation by mitogens and during the cellular response to stress (10,12,17,18), signal pathways leading to MKP-1 gene expression are not fully elucidated.In vivo, vessel walls are exposed to three main hemodynamic forces: shear stress, the dragging frictional force created by blood flow; transmural pressure, created by the hydrostatic forces of blood within the blood vessel; and mechanical stretch or tension, a cyclic strain stress created by blood pressure (19,20). VSMCs are one of the major constituents of blood vessel wall responsible for the maintenance of vascular tone (21). Factors ranging from physical exertion to psychological stress lead to a transient rise in blood pressure (22,23), and if the factors are persistent and chronic, the arteriole walls gradually thicken, resulting in hypertension (22)(23)(24)(25). In humans, atherosclerotic lesions occur preferentially at bifurcations and curvatures (26), where hemodynamic force is disturbed (27). There is growing evidence that mechanical force initiates intracellular signaling and regulates the synthesis and/or secretion of numerous factors, including NO (28), prostacyclin (29), endothelin-1 (30), platelet-derived growth factor, fibroblast growth factor (31, 32), and angiotensin II (33, 34), which are crucial factors in maintaining the homeostasis of the vessel wall. Thus, mechanical stress plays an important role in the development of hypertension and atherosclerosis (35). Xu et al. (36) have previously shown that ...

Mitogen-activated protein kinases mediate stretch-induced c-fos mRNA expression in myometrial smooth muscle cells

“…Platelet-derived growth factor receptor-␣ is activated in vascular SMCs in response to mechanical stretch in a ligand-independent fashion, leading to ERK2 activation and enhanced AP-1 binding activity (15). Using a general growth factor receptor inhibitor, Li et al (28) showed that ERK activation, but not p38 or JNK activation, was dependent on growth factor receptor activation in vascular SMCs.…”

“…Studies in other cell types that employed in vitro stretch systems have demonstrated that cellular mechanotransduction activates multiple signaling molecules (41), including phospholipase C (PLC)-protein kinase C (PKC) (41), cAMP-protein kinase A (PKA) (8), the Janus kinasesignal transducers and activators of transcription (JAK-STAT) pathways (38), phosphatidylinositol 3-kinase (12), G proteins (13), small GTPases (1), receptor and nonreceptor tyrosine kinases (5,15,20,21,30), and, most notably, members of the mitogen-activated protein kinase (MAPK) family (24,28,42,44).…”

Rapid Development of Vein Graft Atheroma in ApoE-Deficient Mice

“…In grafted veins, mechanical force on the vessel segment suddenly increases more than 10-fold (arterial versus venous blood pressure), which provides a strong stimulus to vascular endothelial and SMCs. 32 We previously demonstrated that acutely elevated blood pressure and mechanical stress activate growth factor receptor-MAPK signal pathways, [33][34][35][36] which are critical in mediating mechanical stress-induced cell apoptosis and proliferation. Hyperlipidemia may be an amplifying factor that exerts its effects on vein graft atherosclerosis in the presence of elevated biomechanical stress.…”

Molecular pathways mediating mechanical signaling in bone

“…Much progress has been made in understanding the mechanical response of cardiovascular tissue where cells function in a dynamic system of pulsatile blood flow that creates shear, tension and pressure waves in expandable tubes at a rate of more than 60 times per minute (1 Hz, or 1 cps). Endothelial cells are known to respond to shear stress and cardiac myocytes to strain with teleologically understandable alterations (Li et al, 1999a;Wung et al, 1999). As well, the response of cells of the kidney (Hirakata et al, 1997;Ingram et al, 1999) and lung (Kulik and Alvarado, 1993), to name but a few other organs, demonstrably respond to their mechanical environments.…”