Distinct Contribution of Global and Regional Angiotensin II Type 1a Receptor Inactivation to Amelioration of Aortopathy in Tgfbr1 (M318R/+) Mice.
Distinct Contribution of Global and Regional Angiotensin II Type 1a Receptor Inactivation to Amelioration of Aortopathy in Tgfbr1 (M318R/+) Mice.
复制标题
全球和区域血管紧张素II型1A受体失活对TGFBR1（M318R/+）小鼠的改善的不同贡献。
DOI：
10.3389/fcvm.2022.936142
复制
发表时间：
2022
影响因子：
3.6
通讯作者：
Gallo MacFarlane, Elena
中科院分区：
文献类型：
--
作者：
Bramel, Emily E.;Bagirzadeh, Rustam;Saqib, Muzna;Creamer, Tyler J.;Espinoza Camejo, Wendy A.;Roker, LaToya Ann;Pardo Habashi, Jennifer;Dietz, Harry C.;Gallo MacFarlane, Elena
血管紧张素II (Ang II) 1型受体（AT1R）信号传导控制着血管系统的生理和病理反应。Loeys-Dietz综合征（LDS）是一种以侵袭性主动脉瘤为特征的遗传性疾病，在LDS小鼠模型中，血管紧张素受体阻滞剂（ARBs）治疗可防止主动脉根部扩张和相关的组织学改变。在这项研究中，我们使用Agtr1a（编码AT1a受体）的种系和条件遗传失活来评估LDS小鼠模型（Tgfbr1M318R/+）中全身和局部AT1R信号衰减对主动脉疾病的影响。研究人员检测了Agtr1a基因失活的种系或Mef2CSHF-Cre介导的Tgfbr1M318R/+小鼠的主动脉直径和组织学特征，后者导致主动脉根部和近端主动脉第二心场（SHF）来源的血统缺失。全身和局部AT1R信号衰减均导致LDS小鼠主动脉根部直径减小和组织形态改善；这些结果与Smad2/3和ERK磷酸化水平降低有关，这是先前与LDS主动脉疾病相关的信号事件。然而，与种系Agtr1a缺失的更完全效果相比，shf来源谱系中的区域AT1a失活导致主动脉直径的减少更为温和，这也与降低血压有关。我们的研究结果表明，AT1R拮抗剂在主动脉疾病临床前模型中的治疗效果取决于区域和全身因素，并表明针对这两个过程的组合方法可能有助于缓解动脉瘤。主动脉根部主要由shf来源的细胞组成，在Loeys-Dietz综合征（Tgfbr1M318R/+）患者和小鼠模型中都是一个对扩张易感性增加的部位。这种增加的风险与AT1a的区域性表达增加有关（红色部分）。在Tgfbr1M318R/+小鼠中，shf特异性（AT1a- shfcko）和种系（AT1anull）的AT1a缺失均可减少主动脉根扩张和相关的组织病理学改变，但后者的作用更为明显。
Angiotensin II (Ang II) type 1 receptor (AT1R) signaling controls both physiological and pathogenetic responses in the vasculature. In mouse models of Loeys-Dietz syndrome (LDS), a hereditary disorder characterized by aggressive aortic aneurysms, treatment with angiotensin receptor blockers (ARBs) prevents aortic root dilation and associated histological alterations. In this study we use germline and conditional genetic inactivation of Agtr1a (coding for the AT1a receptor) to assess the effect of systemic and localized AT1R signaling attenuation on aortic disease in a mouse model of LDS (Tgfbr1M318R/+). Aortic diameters and histological features were examined in control and Tgfbr1M318R/+ mice with either germline or Mef2CSHF-Cre mediated genetic inactivation of Agtr1a, the latter resulting in deletion in second heart field (SHF)-derived lineages in the aortic root and proximal aorta. Both systemic and regional AT1R signaling attenuation resulted in reduction of diameters and improvement of tissue morphology in the aortic root of LDS mice; these outcomes were associated with reduced levels of Smad2/3 and ERK phosphorylation, signaling events previously linked to aortic disease in LDS. However, regional AT1a inactivation in SHF-derived lineages resulted in a more modest reduction in aortic diameters relative to the more complete effect of germline Agtr1a deletion, which was also associated with lower blood pressure. Our findings suggest that the therapeutic effects of AT1R antagonisms in preclinical models of aortic disease depend on both regional and systemic factors and suggest that combinatorial approaches targeting both processes may prove beneficial for aneurysm mitigation. The aortic root, which is composed primarily of SHF-derived cells, is a site of increased susceptibility to dilation in both patients and mouse models of Loeys-Dietz Syndrome (Tgfbr1M318R/+). This increased risk associates with regionally increased expression of AT1a (shown in red). Both SHF-specific (AT1a-SHFcKO) and germline (AT1anull) deletion of AT1a reduce aortic root dilation and associated histopathological alterations in Tgfbr1M318R/+ mice, with the latter, however, having a more pronounced effect.
登录
查看更多内容
DOI：
10.1161/atvbaha.121.315715
发表时间：
2021-10
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Chen JZ;Sawada H;Ye D;Katsumata Y;Kukida M;Ohno-Urabe S;Moorleghen JJ;Franklin MK;Howatt DA;Sheppard MB;Mullick AE;Lu HS;Daugherty A
通讯作者：
Daugherty A
影响因子：
14.9
作者：
Sanchez-Guerrero E;Midgley VC;Khachigian LM
通讯作者：
Khachigian LM
影响因子：
15.9
作者：
MacFarlane, Elena Gallo;Parker, Sarah J.;Dietz, Harry C.
通讯作者：
Dietz, Harry C.
影响因子：
--
作者：
Roman, Mary J.;Devereux, Richard B.;Weinsaft, Jonathan W.
通讯作者：
Weinsaft, Jonathan W.
影响因子：
9.3
作者：
Kawai T;Forrester SJ;O'Brien S;Baggett A;Rizzo V;Eguchi S
通讯作者：
Eguchi S