Receptor and Molecular Mechanism of AGGF1 Signaling in Endothelial Cell Functions and Angiogenesis.
Receptor and Molecular Mechanism of AGGF1 Signaling in Endothelial Cell Functions and Angiogenesis.
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AGGF1信号在内皮细胞功能和血管生成中的受体和分子机制
DOI：
10.1161/atvbaha.121.316867
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发表时间：
2021-11
期刊：
影响因子：
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通讯作者：
Wang Q
中科院分区：
文献类型：
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作者：
Wang J;Peng H;Timur AA;Pasupuleti V;Yao Y;Zhang T;You SA;Fan C;Yu Y;Jia X;Chen J;Xu C;Chen Q;Wang Q
文本中提供了补充数字内容。目的：血管生成因子 AGGF1（具有 G 补丁和 FHA [叉头相关] 结构域 1 的血管生成因子）与 VEGFA（血管内皮生长因子 A）一样有效地促进血管生成，并调节内皮细胞 (EC) 增殖、迁移、多能成血管细胞和静脉 EC 的规格、造血和血管发育，并在突变时引起血管疾病 Klippel-Trenaunay 综合征。然而，AGGF1 的受体和潜在的分子机制仍有待确定。方法和结果：通过中和抗体的功能阻断研究，我们确定 α5β1 是 EC 上 AGGF1 的受体。 AGGF1 与 α5β1 相互作用并激活 FAK（粘着斑激酶）、Src（原癌基因酪氨酸蛋白激酶）和 AKT（蛋白激酶 B）。每 50 个氨基酸的 12 个连续 N 端缺失和 13 个 C 端缺失的功能分析将 AGGF1 的血管生成结构域映射到氨基酸 604-613 之间的结构域 (FQRDDAPAS)。血管生成结构域是 EC 粘附和迁移、毛细管形成和 AKT 激活所必需的。血管生成结构域的缺失消除了 AGGF1 对治疗性血管生成的影响，并增加了小鼠外周动脉疾病模型中的血流量。含有血管生成结构域的 40 聚体或 15 聚体肽可阻断 AGGF1 功能，然而，含有从 -RDD- 到 -RGD-（经典的 RGD 整联蛋白结合基序）的单个氨基酸突变的 15 聚体肽无法阻断 AGGF1 功能。结论：我们已经确定整合素α5β1是AGGF1的EC受体，并且是AGGF1介导的新的血管生成信号通路α5β1-FAK-Src-AKT。我们的结果确定了 AGGF1 的 FQRDDAPAS 血管生成结构域，对其与 α5β1 和信号传导的相互作用至关重要。
Supplemental Digital Content is available in the text. Objective: Angiogenic factor AGGF1 (angiogenic factor with G-patch and FHA [Forkhead-associated] domain 1) promotes angiogenesis as potently as VEGFA (vascular endothelial growth factor A) and regulates endothelial cell (EC) proliferation, migration, specification of multipotent hemangioblasts and venous ECs, hematopoiesis, and vascular development and causes vascular disease Klippel-Trenaunay syndrome when mutated. However, the receptor for AGGF1 and the underlying molecular mechanisms remain to be defined. Approach and Results: Using functional blocking studies with neutralizing antibodies, we identified α5β1 as the receptor for AGGF1 on ECs. AGGF1 interacts with α5β1 and activates FAK (focal adhesion kinase), Src (proto-oncogene tyrosine-protein kinase), and AKT (protein kinase B). Functional analysis of 12 serial N-terminal deletions and 13 C-terminal deletions by every 50 amino acids mapped the angiogenic domain of AGGF1 to a domain between amino acids 604-613 (FQRDDAPAS). The angiogenic domain is required for EC adhesion and migration, capillary tube formation, and AKT activation. The deletion of the angiogenic domain eliminated the effects of AGGF1 on therapeutic angiogenesis and increased blood flow in a mouse model for peripheral artery disease. A 40-mer or 15-mer peptide containing the angiogenic domain blocks AGGF1 function, however, a 15-mer peptide containing a single amino acid mutation from −RDD- to −RGD- (a classical RGD integrin-binding motif) failed to block AGGF1 function. Conclusions: We have identified integrin α5β1 as an EC receptor for AGGF1 and a novel AGGF1-mediated signaling pathway of α5β1-FAK-Src-AKT for angiogenesis. Our results identify an FQRDDAPAS angiogenic domain of AGGF1 crucial for its interaction with α5β1 and signaling.