Abstract
Mechanically stressed vascular smooth muscle cells (VSMCs) have potential roles in the development of vascular complications. However, the underlying mechanisms are unclear. Using VSMCs cultured from rat thoracic aorta explants, we investigated the effects of mechanical stretch (MS) on the cellular secretion of high mobility group box 1 (HMGB1), a major damage-associated molecular pattern that mediates vascular complications in stressed vasculature. Enzyme-linked immunosorbent assay (ELISA) demonstrated an increase in the secretion of HMGB1 in VSMCs stimulated with MS (0-3% strain, 60 cycles/min), and this secretion was markedly and time-dependently increased at 3% MS. The increased secretion of HMGB1 at 3% MS was accompanied by an increased cytosolic translocation of nuclear HMGB1; the acetylated and phosphorylated forms of this protein were significantly increased. Among various inhibitors of membrane receptors mediating mechanical signals, AG1295 (a platelet-derived growth factor receptor (PDGFR) inhibitor) attenuated MS-induced HMGB1 secretion. Inhibitors of other receptors, including epidermal growth factor, insulin-like growth factor, and fibroblast growth factor receptors, did not inhibit this secretion. Additionally, MS-induced HMGB1 secretion was markedly attenuated in PDGFR-β-deficient cells but not in cells transfected with PDGFR-α siRNA. Likewise, PDGF-DD, but not PDGF-AA, directly increased HMGB1 secretion in VSMCs, indicating a pivotal role of PDGFR-β signaling in the secretion of this protein in VSMCs. Thus, targeting PDGFR-β-mediated secretion of HMGB1 in VSMCs might be a promising therapeutic strategy for vascular complications associated with hypertension.
Highlights
Increased blood pressure alters the blood vessels structurally and functionally, leading to reduced tissue perfusion and further cardiovascular complications [1]
Using Vascular smooth muscle cell (VSMC) cultured from rat thoracic aorta explants, we investigated the effects of mechanical stretch (MS) on the cellular secretion of high mobility group box 1 (HMGB1), a major damage-associated molecular pattern that mediates vascular complications in stressed vasculature
When 3% strain was applied to VSMCs, the secretion of HMGB1 constantly increased until 12 hrs (52.57 ± 5.24-fold, p < 0.01), but the time dependency was not observed in 1% MS
Summary
Increased blood pressure alters the blood vessels structurally and functionally, leading to reduced tissue perfusion and further cardiovascular complications [1]. The prolonged vasoconstriction in a resistant artery has been considered as the main driver of vascular remodeling in hypertension [2]. In response to increased blood pressure, small resistance vessels undergo vascular remodeling. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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