- A study led by Dr. Silvia Martín-Puig uncovers the key role of HIF2 in protecting the cardiovascular system during chronic hypoxia
- The protective function of HIF2 could influence the design of new therapies for pulmonary hypertension
The Oxygen Homeostasis in the Cardiovascular System group, led by Dr. Silvia Martín-Puig at the Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), CSIC-UAM, has recently published a study in Arteriosclerosis, Thrombosis, and Vascular Biology describing the fundamental role of the hypoxia-inducible factor HIF2 in cardiac and pulmonary adaptation to sustained low-oxygen periods, known as chronic hypoxia. The researchers explain how cardiopulmonary signaling mediated by HIF2 prevents excessive vascular proliferation during prolonged hypoxia, ensuring the stability of the microvasculature and the proper function of these essential organs.
Hypoxia is associated with various cardiovascular diseases, such as cardiac hypertrophy and pulmonary hypertension. Previous investigations have shown that HIF2 signaling in pulmonary endothelial cells promotes arterial remodeling and increases right ventricular systolic pressure under low-oxygen conditions, thus contributing to the progression of pulmonary hypertension. As a result, new therapeutic strategies have been proposed based on specific HIF2 inhibitors. However, the lack of studies assessing HIF2 function in other cell types beyond pulmonary endothelium, as well as the absence of research on its role in the heart, makes it difficult to anticipate the systemic consequences of HIF2 inhibition under sustained hypoxia, a characteristic of certain pulmonary diseases.
“Our work focuses on the characterization of a new genetic mouse model in which HIF2 is deleted across the entire vascular lineage of the heart and lungs, including endothelium, pericytes, and smooth muscle cells. This allows us to study a broader cellular spectrum than previously available, helping us predict potential adverse effects of HIF2 inhibitor-based treatments,” explains Teresa Albendea-Gómez, first author of the study.
Using this animal model, the researchers confirmed that the HIF2 mutant is protected against pulmonary arterial remodeling and the subsequent rise in right ventricular systolic pressure, in agreement with previous findings. However, in contrast to this benefit of eliminating HIF2, “our study reveals that in the absence of HIF2, sustained exposure to low-oxygen conditions—a widely accepted protocol for modeling pulmonary hypertension in rodents—leads to severe pulmonary alterations, including pleural thickening, alveolar congestion, inflammation, and pulmonary hemorrhages,” explains Silvia Martín-Puig. “Additionally, HIF2-deficient mice develop cardiomegaly, capillary remodeling, ventricular hypertrophy and chamber dilation, as well as systolic dysfunction, suggesting that HIF2 plays essential cardioprotective roles in hypoxia that are direct and independent of its function in the lungs,” she continues. These structural defects are partially recovered after one week of reoxygenation, but cardiac functional parameters remained altered.
These findings reveal previously unrecognized protective functions of HIF2 and highlight the importance of HIF2-dependent microvascular stability in preventing pulmonary congestion and cardiac dysfunction under hypoxic conditions. Moreover, the study warns of serious cardiovascular complications that could arise from pharmacological treatments using HIF2 inhibitors, which have already been proposed as therapeutic options not only for pulmonary hypertension, but also for certain clear cell renal carcinomas.
This research was conducted in collaboration with the Centro de Investigaciones Biológicas Margarita Salas (CIB-CSIC), the Centro Nacional de Investigaciones Cardiovasculares (CNIC), and the Universidad Complutense de Madrid (UCM). It was funded by the Ministerio de Ciencia e Innovación (PID2020‐117629RB‐I00), the Fundación Domingo Martínez (CARDIO.COM), and the Comunidad de Madrid (P2022/BMD-7245).
Figure. Control animals with intact HIF2 are protected from the development of cardiomegaly (enlarged heart) associated with capillary dilation and endothelial cell proliferation in response to hypoxia (A). However, the loss of HIF2 leads to the onset of secondary cardiomegaly due to capillary dilation and endothelial proliferation, ultimately resulting in cardiac dysfunction under hypoxia (C). On the other hand, the lungs of control animals maintain a preserved alveolar parenchymal structure under hypoxia, although they exhibit significant arterial remodeling (muscularization) mediated by HIF2 (B). In contrast, HIF2-deficient mice are protected from this muscularization and excessive endothelial proliferation but develop severe structural defects such as pulmonary congestion with erythrocytes and macrophages, hemorrhages, and alveolar wall thickening, likely secondary to capillary instability (D). Overall, these results suggest that HIF2 plays an inhibitory role in vascular cells of the heart and lungs, preventing excessive microvascular remodeling and organ dysfunction in response to hypoxia.