Orai1-Mediated Ca²⁺ Signaling Promotes Post-Infarction Angiogenesis Through VEGF and Notch Pathways
Introduction: Neovascularization is crucial for cardiac repair after myocardial infarction (MI), and Ca2+ signaling plays a critical role in endothelial cell (EC) activation.
Aims: Although Orai1-dependent store-operated calcium entry (SOCE) is known to promote angiogenesis, its specific contribution to post-MI neovascularization remains poorly understood.
Methods: To investigate pro-angiogenic mechanisms and mimic the systemic post-infarction environment, we stimulated human umbilical vein endothelial cells with serum from patients with ST-segment elevation myocardial infarction (STEMI). Integrative analyses were performed using transcriptomics, proteomics, and single-cell RNA sequencing (scRNA-seq).
Results: STEMI serum enhanced angiogenic responses in ECs by activating VEGF, Notch, and Ca2+ signaling pathways. Notably, ischemic serum increased Orai1 expression and exacerbated SOCE activity, which was required for EC migration and proliferation. In a mouse model for MI, scRNA-seq revealed augmented Orai1 expression, particularly in tip and proliferating EC clusters. Orai1 expression was further confirmed in in ECs located in peri-infarct regions of the mouse heart. Proteomics analysis demonstrated that Orai1 silencing dysregulated the expression of VEGF and Notch1-related pro-angiogenic proteins. Furthermore, interleukin-17A (IL-17A) mimicked the effects of patients serum by inducing Orai1-mediated SOCE and promoting ECs migration.
Conclusions: These findings identify a novel role for Orai1-dependent mechanism in post-MI angiogenesis, highlighting Orai1 as a promising therapeutic target for cardiac repair.