Biology subjects

Menendez-Montes, I.

Publications and source records attributed to Menendez-Montes, I..

4 recordsLinked to original sources

bioRxiv2024

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

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.

pathology↗

bioRxiv2021

Angiocrine IGFBP3 Spatially Coordinates IGF Signaling During Neonatal Cardiac Regeneration

To identify non-cell-autonomous effectors of cardiomyocyte mitosis, we analyzed a transcriptomic screen of regenerating and non-regenerating neonatal hearts for differentially-expressed secreted proteins - which we hypothesized could include candidate mitogens. We identified and validated IGFBP3, which has a Janus-like stabilizing and sequestering effect on IGF growth factors, as a neonatal injury-associated secreted protein. IGFBP3 is expressed by and secreted from vascular cells in the neonatal heart after cardiac injury, notably in the infarct border zone. We found that global deletion of IGFBP3 blunted neonatal regeneration, while gain-of-function experiments using recombinant IGFBP3 and a transgenic mouse model uncovered a pro-mitotic effect of IGFBP3 on cardiomyocytes in vitro and in the adult heart. We show that site-specific expression of an IGFBP3 protease (PAPP-A2) and its inhibitor (STC2) coordinate the spatial release of IGF2 in the infarct zone to regio-selectively activate the INSR-ERK-AKT cell growth pathways in cardiomyocytes. Collectively, our work highlights the spatiotemporal orchestration of endothelial-cardiomyocyte interactions that are required for neonatal cardiac regeneration.

cell biology↗

bioRxiv2020

Activation of amino acid metabolic program in response to impaired glycolysis in cardiac HIF1 deficient mice

Hypoxia is an important environmental cue in heart development. Despite of extensive characterization of gain and loss of function models, there is disagreement about the impact of HIF1 elimination in cardiac tissue. Here, we used a new conditional knock out of Hif1a in NKX2.5 cardiac progenitors to assess the morphological and functional consequences of HIF1 loss in the developing heart. By combining histology, electron microscopy and high-throughout genomics, proteomics and metabolomics, we found that deletion of Hif1a leads to impaired embryonic glycolysis without influencing cardiomyocyte proliferation and results in an increased mitochondrial number, activation of a transient amino acid response and upregulation of HIF2 and ATF4 by E12.5. Hif1a mutants display normal fatty acid oxidation metabolic profile and do not show any sign of cardiac dysfunction in the adulthood. Our results demonstrate that HIF1 signaling is dispensable for heart development and reveal the metabolic flexibility of the embryonic myocardium, opening the potential application of alternative energy sources as therapeutic interventions during ischemic events.

developmental biology↗

bioRxiv2019

Metabolic reprogramming from glycolysis to amino acid utilization in cardiac HIF1α deficient mice.

RationaleHypoxia is an important environmental cue implicated in several physiopathological processes, including heart development. Several mouse models of activation or inhibition of hypoxia have been previously described. While gain of function models have been extensively characterized and indicate that HIF1 signaling needs to be tightly regulated to ensure a proper cardiac development, there is lack of consensus in the field about the functional outcomes of HIF1 loss.\n\nObjectiveIn this study, we aim to assess the consequences of cardiac deletion of HIF1 during heart development and identify the cardiac adaptations to HIF1 loss.\n\nMethods and ResultsHere, we used a conditional deletion model of Hif1a in NKX2.5+ cardiac progenitors. By a combination of histology, electron microscopy, massive gene expression studies, proteomics, metabolomics and cardiac imaging, we found that HIF1 is dispensable for cardiac development. Hif1a loss results in glycolytic inhibition in the embryonic heart without affecting normal cardiac growth. However, together with a premature increase in mitochondrial number by E12.5, we found global upregulation of amino acid transport and catabolic processes. Interestingly, this amino acid catabolism activation is transient and does not preclude the normal cardiac metabolic switch towards fatty acid oxidation (FAO) after E14.5. Moreover, Hif1a loss is accompanied by an increase in ATF4, described as an important regulator of several amino acid transporters.\n\nConclusionsOur data indicate that HIF1 is not required for normal cardiac development and suggest that additional mechanisms can compensate Hif1a loss. Moreover, our results reveal the metabolic flexibility of the embryonic heart at early stages of development, showing the capacity of the myocardium to adapt its energy source to satisfy the energetic and building blocks demands to achieve normal cardiac growth and function. This metabolic reprograming might be relevant in the setting of adult cardiac failure.

developmental biology↗