炎症诱导的管周脂肪功能紊乱参与高血压血管损伤的作用机制

Perivascular adipose tissue (PVAT) play notable roles in maintaining vascular homeostasis. A better understanding of the basis and implicated mechanisms involved in the imbalance of vascular homeostasis is essential to developing the prevention and treatment of vascular injury. Preliminary studies of the present project showed evidence that the active complement 5a (C5a) released upon the activation of the complement system mediated macrophage polarization toward a pro-inflammatory M1 phenotype in PVAT and was involved in hypertension-related vascular inflammation. (2015 ATVB) However, C5a inhibition only partially attenuated vascular remodeling and did not reverse vasomotor dysfunction. Further research revealed that, following vascular injury, perivascular adipocytes underwent morphological changes, with extensive macrophage infiltration and an increase in the inflammasome NLRP3, which inhibited the β3 adrenoreceptor (ADRB3) in adipocytes, further aggravating vascular injury (see work basis). Thus we hypothesize that the disrupted secretion of vasomotor factors in adipocytes induced by inflammation may be an important cause of vascular dysfunction. Accordingly we design this study in the context of perivascular adipocytes, using hypertensive models to investigate firstly, the molecular mechanism of perivascular immunocytes activating and inducing adipocyte dysfunction and releasing abnormal vasoactive factors; secondly, the signaling mechanism of inflammatory cytokines mediating the vascular dysfunction involving adipocyte ADRB3; and finally, the intervention of NLRP3-mediated PVAT dysfunction to ameliorate vascular injury. Taken together, we present a novel therapeutic strategy and potential target for intervention to advance the prevention and control of hypertensive vascular diseases.

血管外周脂肪组织在维持血管稳态中起重要作用，阐明管周脂肪介导的血管稳态失衡作用机制对防治血管损伤至关重要。本项目前期研究发现管周脂肪补体活性介质C5a通过促进巨噬细胞向促炎表型分化参与高血压血管损伤。但是抑制C5a仅部分改善血管重塑，不能逆转血管舒缩功能异常。进一步研究发现血管损伤时巨噬细胞NLRP3炎症小体增多, 伴随管周脂肪细胞形态变化，β3肾上腺素能受体（ADRB3）表达增加，抑制ADRB3加重血管损伤。由此假设炎症-免疫激活诱导脂肪细胞功能紊乱可能是导致血管功能异常的重要因素。为证实这一假说，本研究以高血压模型为研究对象，以管周脂肪细胞为切入点，研究1）管周巨噬细胞极化诱导脂肪细胞释放异常血管活性物质的分子机制；2）炎症因子调控脂肪细胞ADRB3参与血管舒缩功能紊乱的信号机制；3）干预炎症小体调控的管周脂肪功能紊乱改善血管损伤，为防治高血压血管病变提供新的治疗策略与干预靶点。

管外周脂肪组织在维持血管稳态中起重要作用，阐明管周脂肪介导的血管稳态失衡作用机制对防治血管损伤至关重要。本项目前期研究发现管周脂肪补体活性介质C5a通过促进巨噬细胞向促炎表型分化参与高血压血管损伤。但是抑制C5a仅部分改善血管重塑，不能逆转血管舒缩功能异常。进一步研究发现血管损伤时巨噬细胞炎症反应伴随管周脂肪细胞形态变化。因此本研究以高血压模型为研究对象，以管周脂肪细胞为切入点，发现1）补体介导的免疫炎症反应参与血压调节及高血压血管损伤；2）衰老诱导的血管外周脂肪棕色化能力降低抑制对血管舒张功能；3）棕色脂肪合成FGF21通过内分泌作用参与抑制高血压靶器官损伤；4）SIRT3通过抑制内皮间质转分化改善高血压肾纤维化；5)管周脂肪因子PDGF-D通过促进炎症反应参与高血压血管损伤过程的调控。以上研究为防治高血压血管病变寻找新的治疗策略与干预靶点提供了理论基础。