腹主動脈瘤（abdominal aortic aneurysm, AAA）是一種常見的退化性血管疾病，其特徵為腹主動脈逐漸擴張，並在破裂後導致極高的死亡率。此疾病的病理特徵為中層結構的破壞與血管平滑肌細胞（vascular smooth muscle cells, VSMCs）的喪失，而VSMCs在合成與維持細胞外基質（extracellular matrix, ECM）結構中扮演關鍵角色。多條訊息傳導途徑，如MAPK、JAK/STAT與TGF-β等，皆與主動脈瘤的形成有關。CD248最初在內皮細胞中被發現，但其實主要高表現在周細胞、血管平滑肌細胞與成纖維細胞中，並參與細胞活化、增生與遷移的調控。這些細胞共同構成血管壁，然而CD248在心血管疾病中的角色仍不明確。
我們的初步研究發現，在主動脈瘤患者的主動脈中層與外層中，CD248的表現量顯著上升。因此，我們推測CD248可能因其協調多種膜受體的多效性（pleiotropic nature），參與主動脈瘤的進程。首先，我們分析了CD248在Ang II誘發動脈瘤小鼠模式與主動脈瘤患者之主動脈中的表現情形。結果顯示，在中層平滑肌細胞與外層成纖維細胞中，CD248皆有顯著上調。為進一步探討其功能，我們利用Cd248基因缺失小鼠，經Ang II輸注並合併高膽固醇飲食誘發主動脈瘤發生，觀察其血管結構與病理變化。結果顯示，Cd248基因缺失會加劇Ang II誘發的腹主動脈瘤形成。
為闡明其機制，我們進一步檢測Cd248基因缺失是否影響膠原蛋白型別轉換、Ang II訊息傳導及發炎狀態。雖然在Cd248基因缺失小鼠的腹主動脈瘤組織中觀察到代償性細胞外基質沉積，但卻缺乏主要承受張力的膠原成分。此外，p38 MAPK的活化在Cd248基因缺失的腹動脈瘤組織中顯著下降，顯示Ang II介導的訊息傳導受損。為探討細胞特異性反應，我們分別在A7r5平滑肌細胞與C3H10T1/2成纖維細胞中分析CD248表現，並進行Cd248基因沉默與Ang II刺激實驗。結果顯示，CD248缺失主要影響平滑肌細胞的功能反應，而對成纖維細胞影響較小。進一步分析顯示，在平滑肌細胞中，CD248缺失會降低膜上受體（包括Ang II型1受體與PDGF受體）的穩定性，進而削弱Ang II與PDGF-BB誘導的訊息傳導及功能反應。且CD248的C端結構域可能是介導膜受體交互作用的關鍵結構元件。
綜合以上所述，本研究揭示CD248作為一種新穎跨膜共受體，參與血管重塑相關的病理機制，並提出以CD248為靶點的潛在藥理策略，用以治療主動脈瘤。

Abdominal aortic aneurysm (AAA) is a prevalent degenerative disease characterized by the progressive widening of the abdominal aorta and substantial mortality upon rupture. This disorder is pathologically characterized by the medial destruction and loss of vascular smooth muscle cells (VSMCs), which are crucial for synthesizing and maintaining the extracellular matrix (ECM) structure. Many signaling pathways, such as MAPKs, JAK/STAT, and TGF-β, have been linked to the development of aortic aneurysm. CD248 was originally identified in endothelial cells; however, it is highly expressed in pericytes, VSMCs, and fibroblasts and is associated with the regulation of cellular activation, proliferation, and migration. Vessels are composed of these cell types. However, the role of CD248 in cardiovascular diseases remains unclear. Our preliminary results showed dramatic upregulation of CD248 in the aortic media and adventitia of patients with aortic aneurysms. Therefore, we hypothesized that CD248 participates in the progression of aortic aneurysms owing to its pleiotropic nature in coordinating several membrane receptors. We first examined the expression of CD248 in the aortas of Ang II-treated mice and in patients with AAA. CD248 was dramatically upregulated in the medial smooth muscle and adventitial fibroblast layers in both patients and an animal model of AAA. To further explore the functional role of CD248, we utilized Cd248-deficient mice to induce aortic aneurysm via Ang II infusion combined with a high-cholesterol diet and then assessed their aortic structure and pathological changes. Interestingly, Cd248 deletion exacerbated Ang II-induced AAA in vivo. To elucidate the underlying mechanisms, we investigated whether Cd248 deficiency affected collagen type switching, Ang II signaling, and the inflammatory status in Cd248-knockout mice. Although compensatory ECM deposition was observed in the aneurysms of Cd248 knockout mice, it lacked the main load-bearing collagen components. Moreover, p38 MAP activation was significantly attenuated in Cd248-deficient aneurysmal tissues, suggesting impaired Ang II-mediated signaling. To explore cell-type-specific responses to Ang II, CD248 expression was evaluated in A7r5 VSMCs and C3H10T1/2 fibroblasts. Subsequently, Cd248 knockdown followed by Ang II stimulation was performed to identify the downstream molecular targets involved in Ang II-mediated signaling in vitro. Our data suggest a cell type-specific effect, with notable dysfunction in VSMCs, but not in fibroblasts. Interestingly, CD248 deficiency impaired the stability of membrane-bound receptors, including the angiotensin II type 1 receptor and platelet-derived growth factor receptors, in VSMCs, thereby blunting the signaling and functional responses elicited by Ang II and PDGF-BB. Furthermore, the C-terminal intracellular domain of CD248 could serve as a critical structural element required for the mediation of membrane receptors. Overall, our study suggests CD248 as a novel transmembrane co-receptor involved in the pathogenesis of vascular remodeling. This study also proposes a potential pharmacological strategy targeting CD248 for the treatment of aortic aneurysms.

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