NLGN3 contributes to angiogenesis in myocardial infarction via activation of the Gαi1/3-Akt Pathway

Study objective: Angiogenesis is an important repair mechanism for myocardial infarction. Neuroligin-3 (NLGN3) can promote angiogenesis by activating Gαi1/3-Akt signaling following ischemic brain injury. This study investigated the role of NLGN3 in myocardial infarction (MI). Hypothesis: Endothelial NLGN3-Gαi1/3 signaling pathway promotes angiogenesis and reduces the ischemic area following MI Methodology: Adult Gαi1/3 knockout (Gαi1/3-KO) mouse were then anesthetized with an intraperitoneal injection of tribromoethanol (400 mg/kg), ventilated with a rodent ventilator, and then the left anterior descending (LAD) coronary artery was permanently occluded. Echocardiography was performed before myocardial infarction modeling and repeated at 1, 7, 14, and 28 days after myocardial infarction. Cardiac endothelial cells were initially cultured to explore the regulatory mechanism of NLGN3 on angiogenesis. Data and Result: On the 7 th day after MI, the plasma level of NLGN3 in MI mice was significantly higher than in the control group. A mouse model of MI also showed significantly increased expression of NLGN3 in heart tissue. Single-nucleus transcriptome analysis revealed that NLGN3 was located predominantly in cardiac fibroblasts and endothelial cells (ECs). Endothelial-specific knockdown of NLGN3, or inhibition of NLGN3 using ADAM10i, significantly increased the ischemic area, reduced angiogenesis, and worsened cardiac function. Co-immunoprecipitation (Co-IP) experiments showed that NLGN3 interacted with Gαi1/3. The Gαi1/3 knockout (Gαi1/3-KO) mouse model of MI showed an increased ischemic area, decreased angiogenesis, and impaired cardiac function. Mechanistic studies showed that the NLGN3-Gαi1/3 signaling pathway exerts cardioprotective effects by promoting EC proliferation and tube formation through the PI3K-Akt-mTOR pathway. Silencing of Gαi1/3 largely eliminated the ability of NLGN3-promoting cardiac ECs to proliferate and form tubes. This work was supported by National Natural Science Foundation of China, No. 82170831. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.