LRP1 protects against excessive superior mesenteric artery remodeling by modulating angiotensin II-mediated signaling.
LRP1 protects against excessive superior mesenteric artery remodeling by modulating angiotensin II-mediated signaling.
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DOI：
10.1172/jci.insight.164751
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发表时间：
2023-01-24
期刊：
影响因子：
8
通讯作者：
Strickland, Dudley K.
中科院分区：
文献类型：
--
作者：
Zhang, Jackie M.;Au, Dianaly T.;Sawada, Hisashi;Franklin, Michael K.;Moorleghen, Jessica J.;Howatt, Deborah A.;Wang, Pengjun;Aicher, Brittany O.;Hampton, Brian;Migliorini, Mary;Ni, Fenge;Mullick, Adam E.;Wani, Mashhood M.;Ucuzian, Areck A.;Lu, Hong S.;Muratoglu, Selen C.;Daugherty, Alan;Strickland, Dudley K.
血管平滑肌细胞（vSMC）在感知和维持血管完整性方面发挥着关键作用。这些细胞大量表达低密度脂蛋白受体相关蛋白1（LRP 1），这是一种大型内吞信号受体，可识别多种配体，包括富含载脂蛋白E的脂蛋白、蛋白酶和蛋白酶抑制剂复合物。我们观察到自发形成的动脉瘤的上级肠系膜动脉（SMA）的雄性和雌性小鼠中，LRP 1基因缺失的vSMC（smLRP 1-/-小鼠）。定量蛋白质组学显示，已知由血管紧张素II介导的（AngII介导的）信号转导诱导的smLRP 1-/-小鼠中几种蛋白质丰度升高，表明该途径失调。给予氯沙坦、AngII I型受体拮抗剂或血管紧张素原反义寡核苷酸以降低血浆血管紧张素原浓度可恢复smLRP 1-/-小鼠的正常SMA表型并预防动脉瘤形成。此外，使用血管损伤模型，我们注意到smLRP 1-/-小鼠过度的血管重塑和新生内膜形成，氯沙坦给药后恢复。总之，这些发现表明LRP 1通过减弱过度的AngII介导的信号传导来调节血管完整性和SMA的重塑。
Vascular smooth muscle cells (vSMCs) exert a critical role in sensing and maintaining vascular integrity. These cells abundantly express the low-density lipoprotein receptor–related protein 1 (LRP1), a large endocytic signaling receptor that recognizes numerous ligands, including apolipoprotein E–rich lipoproteins, proteases, and protease-inhibitor complexes. We observed the spontaneous formation of aneurysms in the superior mesenteric artery (SMA) of both male and female mice in which LRP1 was genetically deleted in vSMCs (smLRP1–/– mice). Quantitative proteomics revealed elevated abundance of several proteins in smLRP1–/– mice that are known to be induced by angiotensin II–mediated (AngII-mediated) signaling, suggesting that this pathway was dysregulated. Administration of losartan, an AngII type I receptor antagonist, or an angiotensinogen antisense oligonucleotide to reduce plasma angiotensinogen concentrations restored the normal SMA phenotype in smLRP1–/– mice and prevented aneurysm formation. Additionally, using a vascular injury model, we noted excessive vascular remodeling and neointima formation in smLRP1–/– mice that was restored by losartan administration. Together, these findings reveal that LRP1 regulates vascular integrity and remodeling of the SMA by attenuating excessive AngII-mediated signaling.
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影响因子：
3.7
作者：
Boucher, Philippe;Li, Wei-Ping;Matz, Rachel L.;Takayama, Yoshiharu;Auwerx, Johan;Anderson, Richard G. W.;Herz, Joachim
通讯作者：
Herz, Joachim
影响因子：
9.8
作者：
Bown, Matthew J.;Jones, Gregory T.;Samani, Nilesh J.
通讯作者：
Samani, Nilesh J.
影响因子：
--
作者：
Bradley, Declan T.;Hughes, Anne E.;Bown, Matthew J.
通讯作者：
Bown, Matthew J.
影响因子：
2.7
作者：
Benjamini, Yoav;Krieger, Abba M.;Yekutieli, Daniel
通讯作者：
Yekutieli, Daniel
DOI：
10.1016/j.bbrc.2014.10.092
发表时间：
2014-11-07
影响因子：
3.1
作者：
Gao, Fu;Chambon, Pierre;Li, Wei
通讯作者：
Li, Wei