VEGF通过磷酸化MASP1调节补体系统活化在HELLP综合征发病中的机制研究

HELLP综合征是妊娠期高血压疾病最严重的表现类型。我们前期研究发现，补体系统异常活化参与了HELLP综合征的发病过程，其活化程度与sflt-1有明显相关性。为进一步探讨sflt-1与补体系统活化之间的关系，我们通过外显子测序发现33%的HELLP综合征患者存在补体活化凝集素途径MASP1杂合突变T507M，而VEGF通路可以通过磷酸化该位点抑制补体系统经凝集素途径的活化。我们推测：HELLP综合征患者高表达的sflt-1使VEGF功能下降，伴随MASP1基因T507M杂合突变，使得VEGF通路无法磷酸化该位点，导致补体系统异常活化。为证实该推测，我们拟通过外显子测序建立HELLP综合征患者补体系统基因突变谱；在细胞学水平明确VEGF通路通过磷酸化MASP1调控补体凝集素途径的机制；在动物水平探讨靶向补体系统在HELLP综合征治疗中的作用。希望为HELLP综合征发病机制提供新的补充。

HELLP syndrome is the most serious manifestation of hypertensive disease in pregnancy. Our previous study found that aberrant activation of the complement system plays a critical role in the pathogenesis of HELLP syndrome, and the degree of complement activation was significantly related to levels of sflt-1. To further explore the relationship between sflt-1 and complement activation, we performed exome sequencing, and found that 33% of patients with HELLP syndrome had heterozygous T507M mutation of MASP1 gene, which is an important protein involved in lectin pathway of complement system. Furthermore, we showed VEGF pathway could inhibit complement system activation via lectin pathway by AKT-mediated phosphorylation of MASP1 at T507. According to these data, we speculate that high expression of sflt-1 in patients with HELLP syndrome inhibit the function of VEGF, accompanied by heterozygous mutations in MASP1 genes, make the VEGF pathway unable to phosphorylate MASP1 at T507, which subsequently leads to the aberrant activation of the complement system. To prove this hypothesis, we proposed to establish gene mutation profiles of complement system in patients with HELLP syndrome by exome sequencing; to clarify the mechanism of VEGF pathway regulating complement lectin pathway through phosphorylation MASP1 in cells; and to explore the effect of inhibiting complement activation in the treatment of HELLP syndrome at animal level. This study may uncover the mechanism underlying complement system activation in the pathogenesis of HELLP syndrome.