Browsing by Subject "vascular smooth muscle cells"

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    Complex Role for E-Prostanoid 4 Receptors in Hypertension.
    (Journal of the American Heart Association, 2019-02) Herrera, Marcela; Yang, Ting; Sparks, Matthew A; Manning, Michael W; Koller, Beverly H; Coffman, Thomas M
    Background Prostaglandin E2 ( PGE 2) is a major prostanoid with multiple actions that potentially affect blood pressure ( BP ). PGE 2 acts through 4 distinct E-prostanoid ( EP ) receptor isoforms: EP 1 to EP 4. The EP 4 receptor ( EP 4R) promotes PGE 2-dependent vasodilation, but its role in the pathogenesis of hypertension is not clear. Methods and Results To address this issue, we studied mice after temporal- and cell-specific deletion of EP 4R. First, using a mouse line with loss of EP 4 expression induced universally after birth, we confirm that EP 4R mediates a major portion of the acute vasodilatory effects of infused PGE 2. In addition, EP 4 contributes to control of resting BP , which was increased by 5±1 mm Hg in animals with generalized deficiency of this receptor. We also show that EP 4 is critical for limiting elevations in BP caused by high salt feeding and long-term infusion of angiotensin II . To more precisely identify the mechanism for these actions, we generated mice in which EP 4R loss is induced after birth and is limited to smooth muscle. In these mice, acute PGE 2-dependent vasodilation was attenuated, indicating that this response is mediated by EP 4R in vascular smooth muscle cells. However, absence of EP 4R only in this vascular compartment had a paradoxical effect of lowering resting BP , whereas the protective effect of EP 4R on limiting angiotensin II-dependent hypertension was unaffected. Conclusions Taken together, our findings support a complex role for EP 4R in regulation of BP and in hypertension, which appears to involve actions of the EP 4R in tissues beyond vascular smooth muscle cells.
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    Drebrin attenuates atherosclerosis by limiting smooth muscle cell transdifferentiation.
    (Cardiovascular research, 2021-04-29) Wu, Jiao-Hui; Zhang, Lisheng; Nepliouev, Igor; Brian, Leigh; Huang, Taiqin; Snow, Kamie P; Schickling, Brandon M; Hauser, Elizabeth R; Miller, Francis J; Freedman, Neil J; Stiber, Jonathan A

    Aims

    The F-actin-binding protein Drebrin inhibits smooth muscle cell (SMC) migration, proliferation and pro-inflammatory signaling. Therefore, we tested the hypothesis that Drebrin constrains atherosclerosis.

    Methods and results

    SM22-Cre+/Dbnflox/flox/Ldlr-/- (SMC-Dbn-/-/Ldlr-/-) and control mice (SM22-Cre+/Ldlr-/-, Dbnflox/flox/Ldlr-/-, and Ldlr-/-) were fed a Western diet for 14-20 weeks. Brachiocephalic arteries of SMC-Dbn-/-/Ldlr-/- mice exhibited 1.5- or 1.8-fold greater cross-sectional lesion area than control mice at 14 or 20 wk, respectively. Aortic atherosclerotic lesion surface area was 1.2-fold greater in SMC-Dbn-/-/Ldlr-/- mice. SMC-Dbn-/-/Ldlr-/- lesions comprised necrotic cores that were two-fold greater in size than those of control mice. Consistent with their bigger necrotic core size, lesions in SMC-Dbn-/- arteries also showed more transdifferentiation of SMCs to macrophage-like cells: 1.5- to 2.5-fold greater, assessed with BODIPY or with CD68, respectively. In vitro data were concordant: Dbn-/- SMCs had 1.7-fold higher levels of KLF4 and transdifferentiated to macrophage-like cells more readily than Dbnflox/flox SMCs upon cholesterol loading, as evidenced by greater up-regulation of CD68 and galectin-3. Adenovirally mediated Drebrin rescue produced equivalent levels of macrophage-like transdifferentiation in Dbn-/- and Dbnflox/flox SMCs. During early atherogenesis, SMC-Dbn-/-/Ldlr-/- aortas demonstrated 1.6-fold higher levels of reactive oxygen species than control mouse aortas. The 1.8-fold higher levels of Nox1 in Dbn-/- SMCs was reduced to WT levels with KLF4 silencing. Inhibition of Nox1 chemically or with siRNA produced equivalent levels of macrophage-like transdifferentiation in Dbn-/- and Dbnflox/flox SMCs.

    Conclusions

    We conclude that SMC Drebrin limits atherosclerosis by constraining SMC Nox1 activity and SMC transdifferentiation to macrophage-like cells.

    Translational perspective

    Drebrin is abundantly expressed in vascular smooth muscle cells (SMCs) and is up-regulated in human atherosclerosis. A hallmark of atherosclerosis is the accumulation of foam cells that secrete pro-inflammatory cytokines and contribute to plaque instability. A large proportion of these foam cells in humans derive from SMCs. We found that SMC Drebrin limits atherosclerosis by reducing SMC transdifferentiation to macrophage-like foam cells in a manner dependent on Nox1 and KLF4. For this reason, strategies aimed at augmenting SMC Drebrin expression in atherosclerotic plaques may limit atherosclerosis progression and enhance plaque stability by bridling SMC-to-foam-cell transdifferentiation.