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Biomechanical strain regulation of vascular smooth muscle cell (VSMC) cytokine secretion and MAPK
Author(s) -
Schad Joseph Francis,
Meltzer Kate Rachel,
Standley Paul R.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.lb97-d
Subject(s) - medicine , endocrinology , mapk/erk pathway , vascular smooth muscle , secretion , chemistry , strain (injury) , phosphorylation , microbiology and biotechnology , biology , smooth muscle
The vessel wall remodels in response to hemodynamic and biomechanical strain. Specifically, VSMC hypertrophy and proliferation occur in response to local / systemic inflammatory cytokines and growth factors and contribute to development of hypertension, atherosclerosis and restenosis. We sought to identify key mediators of such responses in heterobiaxially strained (1 Hz at 115% L o for 1, 6, 18, or 48 hrs) VSMC. Strained cells exhibited attenuated proliferative responses and enhanced protein:DNA 48 hrs post‐strain (p<0.05). Protein arrays revealed that VEGF, MCP‐1, Leptin, IL‐4, IL‐1β, GM‐CSF, Fractalkine, CNTF, and CINC‐3 secretion significantly increased due to strain (p<0.05). ELISA corroborated VEGF increases ≈60% (p<0.05). Nitric oxide (NO) levels increased ≈70% 48 hrs post‐strain. Antibody microarrays of VSMC lysates revealed 46 cellular proteins and/or phosphorylation sites (of 600) that changed ± 1.5‐fold. Of interest, MAPK cascade members including phospho‐MEK4 S257+T261 , MEK2, MEK1, phospo‐MEK1 T385,T291,T297 , phospho‐MAPKAPK2 T334 , MAPK14, phospho‐Erk1/2 T202+Y204/T185+T187 , and phospho‐Erk1/2 T202+T204 were universally increased, suggesting a proliferative / inflammatory signaling state. Therefore, biomechanical strain mimicking arterial pressure waveforms induces the secretion of antimitogenic cytokines including VEGF and NO, but dichotomously stimulates multiple MAPK signals. Whether VEGF and/or NO inhibit this pathway distal to Erk1/2 is to be determined. Funding: NIH grant # P‐01 AT2023 (PRS) and Midwestern University