Angiogenesis is a fundamental mechanism in the development and disease of the cardiovascular system, enabling the formation of collateral vessels and tissue repair. It is a key player in coronary artery disease (CAD), a condition characterized by progressive narrowing of the coronary arteries that can lead to myocardial infarction or stroke. Genetic predisposition contributes significantly to CAD risk, and genome-wide association studies have identified MIA3 and AIDA at 1q41 as CAD-associated genes. However, their functional roles in angiogenesis and cardiovascular physiology are still largely unknown.
In this study, we analyzed the role of MIA3 and AIDA in both angiogenesis and cardiac function using combined in vitro and in vivo approaches. In human umbilical vein endothelial cells (HUVECs), siRNA-mediated knockdown of MIA3 resulted in a marked reduction in capillary-like network formation, with significantly reduced total connection length, vessel tip length, and clustering, suggesting impaired endothelial organization and stabilization.
Single-cell RNA sequencing data from the DanioCell Atlas showed that mia3 is predominantly expressed in endothelial, arterial, venous, and myocardial clusters, while aida has more restricted expression in specific vascular subpopulations such as the carotid and lymphatic vessels. Using CRISPR/Cas9-generated zebrafish knockout models, we further investigated the functional consequences of mia3 and aida loss in vivo. In mia3⁻/⁻ larvae, blood flow, linear flow velocity, and angiogenesis in intersegmental vessels were significantly reduced. In contrast, aida⁻/⁻ larvae showed increased blood flow without structural vascular alterations. Cardiac function analysis in myl7:eGFP zebrafish demonstrated that mia3⁻/⁻ larvae exhibited markedly reduced atrial and ventricular contractility, whereas both mia3⁻/⁻ and aida⁻/⁻ mutants showed elevated atrioventricular conduction scores, suggesting impaired electrical signal transmission.
Together, these findings identify MIA3 as a critical regulator of angiogenesis, vascular integrity, and cardiac contractility, while AIDA appears to influence vascular dynamics and electrical conduction. Both genes contribute to cardiovascular homeostasis, offering new mechanistic insights into the genetic basis and pathophysiology of coronary artery disease and highlighting their potential as novel therapeutic targets.
