Hsieh Tai-Tzu, Ku Ya-Chu, Chen Chu-Jen, Kuo Cheng-Hsiang, Chang Bi-Ing, Yu Chien-Hung, Li Yi-Heng, Tsai Pei-Jane, Lin Shu-Wha, Wu Hua-Lin, Luo Chwan-Yau, Tsai Yau-Sheng
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
Clin Transl Med. 2025 May;15(5):e70352. doi: 10.1002/ctm2.70352.
Abdominal aortic aneurysm (AAA) is characterized by progressive dilation of the abdominal aorta that has a high prevalence of death due to aortic rupture. The hallmark of AAA is severe degeneration of the aortic media with the loss of vascular smooth muscle cells (VSMCs), the main source of extracellular matrix (ECM) proteins. CD248 was originally implicated in angiogenesis and tumourigenesis, but its role in the development of AAA remains unclear.
Mice lacking CD248 (Cd248) were generated and evaluated for angiotensin II (Ang II) and high-cholesterol diet feeding induced AAA. Loss-of-function approaches in A7r5 and C3H10T1/2 cells were used to study the involvement of CD248 in the Ang II signalling.
CD248 expression was upregulated in the media and adventitia of patients and mice with aortic aneurysm. CD248 deficiency in mice exacerbates Ang II-induced aortic lesion along with severe disruption of elastic fibres and the VSMC layer. Interestingly, while compensatory ECM deposition was found in the aortic lesion of Cd248 mice, collagen I content and p38 activation were significantly attenuated. Silencing of CD248 in VSMCs downregulated mitogen-activated protein kinase activation and ECM production. Loss of CD248 in VSMCs destabilized the membrane receptors for Ang II and platelet-derived growth factor (PDGF), and the C-terminal cytoplasmic domain of CD248 is apparently involved in this interaction.
The findings reveal that CD248 regulates the stability of the membrane receptors for Ang II and PDGF in VSMCs to transduce signals for collagen production in combating the loss of aortic wall strength during vascular remodelling.
CD248 reduces the occurrence of angiotensin II (Ang II)-induced aortic lesion by facilitating collagen production to provide load-bearing properties to the aortic wall. CD248 regulates the stability of the membrane receptors for Ang II and PDGF in VSMCs. The C-terminal cytoplasmic tail of CD248 is a crucial domain that potentially regulates the stability of Ang II and PDGF receptors. This knowledge can enhance our understanding of how abdominal aortic aneurysm (AAA) can be treated through CD248-mediated signaling to maintain aortic wall strength during the remodeling process.
腹主动脉瘤（AAA）的特征是腹主动脉进行性扩张，因主动脉破裂导致的死亡率很高。AAA的标志是主动脉中膜严重退变，伴有血管平滑肌细胞（VSMC）丧失，而VSMC是细胞外基质（ECM）蛋白的主要来源。CD248最初与血管生成和肿瘤发生有关，但其在AAA发展中的作用仍不清楚。
构建缺乏CD248（Cd248）的小鼠，并评估其在血管紧张素II（Ang II）和高胆固醇饮食诱导的AAA中的情况。采用功能缺失方法研究A7r5和C3H10T1/2细胞中CD248在Ang II信号传导中的作用。
在患有主动脉瘤的患者和小鼠的中膜和外膜中，CD248表达上调。小鼠体内CD248缺乏会加剧Ang II诱导的主动脉病变，同时弹性纤维和VSMC层严重破坏。有趣的是，虽然在Cd248小鼠的主动脉病变中发现了代偿性ECM沉积，但I型胶原蛋白含量和p38激活明显减弱。VSMC中CD248沉默会下调丝裂原活化蛋白激酶激活和ECM产生。VSMC中CD248缺失会使Ang II和血小板衍生生长因子（PDGF）的膜受体不稳定，并且CD248的C末端胞质结构域显然参与了这种相互作用。
研究结果表明，CD248调节VSMC中Ang II和PDGF膜受体的稳定性，以转导胶原蛋白产生的信号，从而在血管重塑过程中对抗主动脉壁强度的丧失。
CD248通过促进胶原蛋白产生为主动脉壁提供承重特性，从而减少血管紧张素II（Ang II）诱导的主动脉病变的发生。CD248调节VSMC中Ang II和PDGF膜受体的稳定性。CD248的C末端胞质尾是一个关键结构域，可能调节Ang II和PDGF受体的稳定性。这些知识可以增进我们对如何通过CD248介导的信号传导治疗腹主动脉瘤（AAA）以在重塑过程中维持主动脉壁强度的理解。
