VSMC-specific EP4 deletion exacerbates angiotensin II-induced aortic dissection by increasing vascular inflammation and blood pressure
VSMC-specific EP4 deletion exacerbates angiotensin II-induced aortic dissection by increasing vascular inflammation and blood pressure
复制标题
VSMC特异性EP4缺失通过增加血管炎症和血压而加剧血管紧张素II诱导的主动脉夹层
DOI：
10.1073/pnas.1902119116
复制
发表时间：
2019-04-23
影响因子：
11.1
通讯作者：
Guan, Youfei
中科院分区：
文献类型：
--
作者：
Xu, Hu;Du, Shengnan;Guan, Youfei
前列腺素E2（PGE 2）在维持血管稳态中起重要作用。其受体，E-前列腺素受体4（EP 4）是动脉导管（DA）生理重塑所必需的。然而，EP 4在病理性血管重塑中的作用在很大程度上仍然未知。我们发现血管平滑肌细胞（VSMC）特异性EP 4基因敲除小鼠（VSMC-EP 4（-/-））慢性血管紧张素II（AngII）灌注后，经常发生主动脉夹层（AD），伴有严重的弹性纤维降解和VSMC去分化。AngII输注的VSMC-EP 4（-/-）小鼠也显示出更严重的血管炎症，单核细胞趋化蛋白-1（MCP-1）表达、巨噬细胞浸润、基质金属蛋白酶-2和-9（MMP 2/9）水平、NADPH氧化酶1（NOX 1）活性和活性氧产生增加。此外，VSMC-EP 4（-/-）小鼠在基础和AngII输注条件下表现出较高的血压。离体和体外研究进一步揭示，VSMC特异性EP 4基因缺陷显著增加AngII引起的肠系膜动脉血管收缩，可能是通过刺激VSMC 5细胞内钙释放。此外，培养的VSMC 5中的EP 4基因消融和EP 4阻断与MCP-1和NOX 1表达的显著增加以及α-SM肌动蛋白（α-SMA）、SM 22 α和SM分化标记基因肌球蛋白重链（SMMHC）水平和血清反应因子（SRF）转录活性的显著降低相关。综上所述，本研究表明，VSMC EP 4对血管稳态至关重要，其功能障碍加剧了AngII诱导的病理性血管重塑。因此，EP 4可能代表治疗AD的潜在治疗靶点。
Prostaglandin E2 (PGE2) plays an important role in vascular homeostasis. Its receptor, E-prostanoid receptor 4 (EP4) is essential for physiological remodeling of the ductus arteriosus (DA). However, the role of EP4 in pathological vascular remodeling remains largely unknown. We found that chronic angiotensin II (AngII) infusion of mice with vascular smooth muscle cell (VSMC)specific EP4 gene knockout (VSMC-EP4(-/-)) frequently developed aortic dissection (AD) with severe elastic fiber degradation and VSMC dedifferentiation. AngII-infused VSMC-EP4(-/-) mice also displayed more profound vascular inflammation with increased monocyte chemoattractant protein-1 (MCP-1) expression, macrophage infiltration, matrix metalloproteinase-2 and -9 (MMP2/9) levels, NADPH oxidase 1 (NOX1) activity, and reactive oxygen species production. In addition, VSMC-EP4(-/-) mice exhibited higher blood pressure under basal and AngII-infused conditions. Ex vivo and in vitro studies further revealed that VSMC-specific EP4 gene deficiency significantly increased AngII-elicited vasoconstriction of the mesenteric artery, likely by stimulating intracellular calcium release in VSMC5. Furthermore, EP4 gene ablation and EP4 blockade in cultured VSMC5 were associated with a significant increase in MCP-1 and NOX1 expression and a marked reduction in a-SM actin (alpha-SMA), SM22 alpha, and SM differentiation marker genes myosin heavy chain (SMMHC) levels and serum response factor (SRF) transcriptional activity. To summarize, the present study demonstrates that VSMC EP4 is critical for vascular homeostasis, and its dysfunction exacerbates AngII-induced pathological vascular remodeling. EP4 may therefore represent a potential therapeutic target for the treatment of AD.