Activation of HIF2 in Cardiac Vasculature Leads to Arterial Remodeling, Dilation, Thrombosis, and Inflammation, Recapitulating Cardiac Involvement in Kawasaki Disease

BACKGROUND: Global Vhl knockout results in vascular defects and early lethality, limiting our knowledge of von Hippel–Lindau/HIF (hypoxia-inducible factor) signaling in coronary vessel formation and homeostasis. The hypoxia pathway has been implicated in cardiovascular diseases characterized by inflammation and vascular remodeling, such as atherosclerosis, but its involvement in Kawasaki disease (KD) remains unknown. Coronary artery dilation and vessel rupture are the most serious complications of KD. However, the molecular mechanisms underlying these cardiac events are not fully understood. We investigated the role of the von Hippel–Lindau/HIF pathway in cardiovascular pathology and its relevance to KD. METHODS: We generated a novel mouse model with genetic hyperactivation of the hypoxia pathway in progenitors contributing to coronary vessels and cardiac fibroblasts. We characterized the model using echocardiography, magnetic resonance imaging, histology, and molecular profiling. In parallel, we examined cardiac tissues from patients with KD with fatal coronary aneurysms for evidence of HIF signaling and inflammation using immunohistochemistry. RESULTS: Mice with conditional deletion of Vhl in Wt1 (Wilms tumor 1)–expressing cells developed normally but exhibited cardiomegaly, vascular abnormalities, progressive coronary artery dilation, pericardial hemorrhage, and systemic inflammation shortly after birth. Histologic analysis revealed coronary arteritis, elastin breaks, vascular remodeling, smooth muscle cell loss, perivascular fibrosis, and frequent intracoronary thrombus formation. In addition, vascular calcification, severe cardiac inflammation, and interstitial hemorrhages were observed, culminating in sudden death between 15 and 20 weeks of age, likely due to vessel rupture. Cardiac transcriptomic profiling identified dysregulated expression of genes involved in extracellular matrix organization, epithelial–mesenchymal transition, angiogenesis, inflammation, coagulation, and calcification, indicating compromised vascular stability and increased remodeling in Vhl conditional knockout mice. Simultaneous deletion of Hif2a rescued both the cardiovascular abnormalities and transcriptomic profile observed in Vhl conditional knockout mice, implicating Hif2 (hypoxia-inducible factor 2) as a key mediator. Human KD cardiac samples showed expression of HIF2 in coronary lesions and surrounding inflammatory infiltrates, confirming hypoxia pathway activation in severe KD. CONCLUSIONS: Our findings establish HIF2 as a central driver of coronary inflammation, vascular remodeling, and thrombotic complications resembling those observed in severe KD. The Vhl /Wt1 conditional knockout mouse model recapitulates key cardiovascular features of KD and offers a valuable platform for mechanistic studies and therapeutic exploration.