血管重构新信号通路的发现

Vascular remodeling is closely associated with hypertension and aging and contributes significantly to development and complications of hypertension such as thoracic aortic aneurysms (TAA). Hypertension is well known to cause remodeling of large and small arteries, which results in increased peripheral resistance, and worsens vascular remodeling, leading to development of aortic aneurysms and other complications. About 66.7% of TAA patients are affected with hypertension, but the molecular mechanism by which hypertension causes vascular remodeling and aortic aneurysms and dissections is not completely known. To date, there are no effective targets for developing effective therapies for vascular remodeling-related diseases such as aortic aneurysms. AGGF1 is a new angiogenic factor cloned by us in 2004. AGGF1 is the first disease causing gene identified for vascular disease Klippel-Trenaunay syndrome, and plays an important role in vasculogenesis, angiogenesis, vein differentiation, and differentiation of mesodermal cells to multipotential hemangioblasts. Recently, we have found that AGGF1 plays a critical role in vascular remodeling. In a pressure-overload-induced vascular remodeling model, the expression level of AGGF1 was significantly reduced. We further found that down-regulation of AGGF1 was a cause of vascular remodeling because tail-vein injection of the AGGF1 protein significantly blocked vascular remodeling in the pressure-overload-induced model. In this project, we plan to utilize our AGGF1 knockout mice to further investigate the critical role of AGGF1 in vascular remodeling, to demonstrate that AGGF1 mediates vascular remodeling by regulating inflammation, and to characterize the AGGF1 signaling transduction pathway responsible for vascular remodeling using a series of in vitro and in vivo molecular and cellular techniques. These studies may identify a brand new signal pathway for vascular remodeling, identify the molecular mechanisms by which AGGF1 regulates vascular remodeling, and identify a new drug target for developing new therapies to treat vascular remodeling-related diseases.

血管重构与高血压，老龄化等生理或病理过程紧密相关。高血压诱导大动脉及小动脉重构，导致外周动脉血管阻力增加，引起主动脉瘤和脑卒中等一系列高血压并发症，但其分子机制仍然不清楚。对于血管重构诱发的并发症，如主动脉瘤的治疗，缺乏有效的干预靶点，治疗手段及预防措施。AGGF1是我们首次发现和克隆的一个新的血管生长因子，在血管生成，静脉发育及成血管母细胞分化调控上起关键作用。 最近我们发现AGGF1在血管重构中起关键作用。在压力诱导的血管重构模型中，重构血管AGGF1表达量显著降低，尾静脉注射AGGF1蛋白显著抑制血管重构。我们拟利用AGGF1敲除鼠进一步确认AGGF1在血管重构中的关键作用，通过分子手段证实AGGF1通过调控炎症反应影响血管重构并分析AGGF1影响血管重构的信号通路。该研究将发现一条调控血管重构的崭新信号通路，诠释AGGF1抑制血管重构的分子机制,发现血管重构一新的治疗靶点。

血管重构与高血压，老龄化等生理或病理过程紧密相关。高血压诱导大动脉及小动脉重构，导致外周动脉血管阻力增加，引起主动脉瘤和脑卒中等一系列高血压并发症，但其分子机制仍然不清楚。对于血管重构诱发的并发症，如主动脉瘤的治疗，缺乏有效的干预靶点，治疗手段及预防措施。AGGF1基因是我们于2004年发现的第一个KTS综合征（骨肥大性静脉曲张综合征）基因。AGGF1基因编码的血管生成因子，蛋白质全长714氨基酸，含一个FHA功能域（Forkhead-associated domain）和一个G-patch功能域，在血管生成，静脉发育及成血管母细胞分化调控上起关键作用。通过该项目研究，我们发现AGGF1在血管重构中起关键作用。在压力诱导的血管重构模型中，重构血管AGGF1表达量显著降低，尾静脉注射AGGF1蛋白显著抑制血管重构。我们利用AGGF1敲除鼠进一步确认了AGGF1在血管重构中的关键作用，通过分子手段证实AGGF1通过调控炎症反应影响血管重构。在Aggf1+/-敲除小鼠中颈动脉血管损伤后，伴随着血管平滑肌细胞增殖变多，新生内膜形成增加。在进行颈动脉导丝损伤手术后，对野生型小鼠和Aggf1+/-敲除小鼠尾静脉注射AGGF1蛋白治疗能调节颈动脉血管平滑肌细胞表型转换，抑制血管损伤后新生内膜形成。在体外实验中，AGGF1通过抑制MEK1/2-ERK1/2-Elk通路显著抑制血管平滑肌细胞增殖，并减少细胞分裂中处于S期的细胞数目。该研究发现了一条调控血管重构的崭新信号通路，诠释了AGGF1抑制血管重构的分子机制,发现了血管重构一新的治疗靶点。