Activation of HIF2 leads to vascular remodeling and inflammation, coronary thrombosis and arterial dilation, recapitulating cardiac involvement of Kawasaki disease.

Escobar, B.; Menendez-Montes, I.; Albendea-Gomez, T.; Mendoza-Tamajon, S.; Castro-Mecinas, R.; Diaz-Diaz, C.; Palacios, B.; Ruiz-Cabello, J.; Jimenez-Borreguero, L. J.; Cid, M. C.; Takahashi, K.; Martin-Puig, S.

doi:10.1101/2024.01.22.576642

bioRxiv · 10.1101/2024.01.22.576642

Activation of HIF2 leads to vascular remodeling and inflammation, coronary thrombosis and arterial dilation, recapitulating cardiac involvement of Kawasaki disease.

Escobar, B.·Menendez-Montes, I.·Albendea-Gomez, T.·Mendoza-Tamajon, S.·Castro-Mecinas, R.·Diaz-Diaz, C.·Palacios, B.·Ruiz-Cabello, J.·Jimenez-Borreguero, L. J.·Cid, M. C.·Takahashi, K.·Martin-Puig, S.

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Abstract

Backgroundglobal deletion of Vhl leads to vascular defects and early lethality, precluding the study of VHL/HIF signaling during coronary formation and homeostasis. Hypoxia pathway has been associated with cardiovascular diseases involving inflammation and vascular remodeling like atherosclerosis, but its role in Kawasaki Disease (KD) remains unknown. Coronary dilatation and vessel rupture are the most serious complications of KD, while the molecular mechanisms underlying these cardiac events remain poorly understood. Here we aim to determine the function of VHL/HIF pathway in the development of cardiovascular defects and its role in KD. MethodsWe generated a new mouse model to genetically hyperactivate hypoxia pathway in progenitors contributing to coronary vessels and cardiac fibroblasts (Vhl/Wt1). We characterized the model by means of echocardiography, magnetic resonance imaging, histological analysis and molecular approaches. Human cardiac tissue from KD individuals suffering fatal coronary aneurysm were screened for HIF signaling and inflammatory markers by immunohistochemistry. Resultsconditional Vhl KO do not undergo developmental abnormalities but displays cardiomegaly and epicardial vascular defects, with cardiac hypertrophy and progressive coronary diameter increase, as well as pericardial hemorrhage and systemic inflammation early after birth. Histological characterization reveals inflammation of coronary arteries, vascular remodeling with elastin breaks and dilatation, increased perivascular fibrosis and smooth muscle cells death, together with high incidence of intracoronary thrombus formation. In addition, the mutants display vascular calcification and severe cardiac inflammation and interstitial hemorrhages, dying suddenly between 15-20 weeks of age due to vessel rupture. Simultaneous elimination of HIF2 and VHL prevents the cardiovascular abnormalities displayed by single cVhl KO, highlighting the essential role of HIF2 in coronary instability and vascular inflammation. Histological characterization of human cardiac samples shows positive signal for HIF1 and specially HIF2, in the coronary lesions and its surroundings in regions with high inflammatory infiltration, confirming the activation of hypoxia signaling in KD patients with cardiovascular complications. ConclusionsOur data demonstrate the importance of HIF2 signaling in the development of coronary inflammation and vascular remodeling and provide new evidences connecting low oxygen tensions with cardiovascular lesions occurring during the onset of the most severe cases of KD. Furthermore, the Vhl/Wt1 mouse generated recapitulates cardiac features of KD with critical heart complications, providing a new platform to uncover unknown aspects of KD pathogenesis.

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Escobar, B., Menendez-Montes, I., Albendea-Gomez, T., Mendoza-Tamajon, S., Castro-Mecinas, R., Diaz-Diaz, C., Palacios, B., Ruiz-Cabello, J., Jimenez-Borreguero, L. J., Cid, M. C., Takahashi, K., Martin-Puig, S.. 2024-01-25. Activation of HIF2 leads to vascular remodeling and inflammation, coronary thrombosis and arterial dilation, recapitulating cardiac involvement of Kawasaki disease.. https://doi.org/10.1101/2024.01.22.576642

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