Althammer Ferdinand, Roy Ranjan K, Kirchner Matthew K, Podpecan Yuval, Helen Jemima, McGrath Shaina, Lira Elba Campos, Stern Javier E
Center for Neuroinflammation and Cardiometabolic Diseases, Georgia State University, Atlanta, GA, USA.
Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany.
Commun Biol. 2024 Nov 19;7(1):1537. doi: 10.1038/s42003-024-07229-8.
Activation of microglia, the resident immune cells of the central nervous system, leading to the subsequent release of pro-inflammatory cytokines, has been linked to cardiac remodeling, autonomic disbalance, and cognitive deficits in heart failure (HF). While previous studies emphasized the role of hippocampal Angiotensin II (AngII) signaling in HF-induced microglial activation, unanswered mechanistic questions persist. Evidence suggests significant interactions between microglia and local microvasculature, potentially affecting blood-brain barrier integrity and cerebral blood flow regulation. Still, whether the microglial-vascular interface is affected in the brain during HF remains unknown. Using a well-established ischemic HF rat model, we demonstrate the increased abundance of vessel-associated microglia (VAM) in HF rat hippocampi, along with an increased expression of AngII AT1a receptors. Acute AngII administration to sham rats induced microglia recruitment to brain capillaries, along with increased expression of TNFα. Conversely, administering an AT1aR blocker to HF rats prevented the recruitment of microglia to blood vessels, normalizing their levels to those in healthy rats. These results highlight the critical importance of a rather understudied phenomenon (i.e., microglia-vascular interactions in the brain) in the context of the pathophysiology of a highly prevalent cardiovascular disease, and unveil novel potential therapeutic avenues aimed at mitigating neuroinflammation in cardiovascular diseases.
小胶质细胞是中枢神经系统中的常驻免疫细胞，其激活导致促炎细胞因子的后续释放，这与心力衰竭（HF）中的心脏重塑、自主神经失衡和认知缺陷有关。虽然先前的研究强调了海马体中血管紧张素II（AngII）信号传导在HF诱导的小胶质细胞激活中的作用，但仍存在未解答的机制问题。有证据表明小胶质细胞与局部微血管之间存在显著相互作用，这可能会影响血脑屏障的完整性和脑血流调节。然而，在HF期间大脑中的小胶质细胞-血管界面是否受到影响仍然未知。使用成熟的缺血性HF大鼠模型，我们证明了HF大鼠海马体中与血管相关的小胶质细胞（VAM）丰度增加，同时AngII AT1a受体的表达也增加。向假手术大鼠急性注射AngII会诱导小胶质细胞向脑毛细血管募集，同时TNFα表达增加。相反，向HF大鼠施用AT1aR阻滞剂可防止小胶质细胞向血管募集，使其水平恢复到健康大鼠的水平。这些结果突出了一种研究较少的现象（即大脑中的小胶质细胞-血管相互作用）在一种高度普遍的心血管疾病病理生理学背景下的至关重要性，并揭示了旨在减轻心血管疾病中神经炎症的新的潜在治疗途径。
