Eunate Gallardo‐Vara

Yale University

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Luisa M. Botella

Centro de Investigaciones Biológicas Margarita Salas

Carmelo Bernabéu

Consejo Superior de Investigaciones Científicas

Daniel M. Greif

Yale University

Lucía Recio-Poveda

Centre for Biomedical Network Research on Rare Diseases

Francisco J. Blanco

Universidad de Granada

ÁM

Ángel M. Cuesta

Universidad Complutense de Madrid

Inamul Kabir

Yale University

Virginia Albiñana

Centre for Biomedical Network Research on Rare Diseases

Eduardo Rial

Centro de Investigaciones Biológicas Margarita Salas

Jui M. Dave

Yale University

Cooperative Institutions

Consejo Superior de Investigaciones Científicas

Centro de Investigaciones Biológicas Margarita Salas

Yale University

Centro de Investigación Biomédica en Red

Centre for Biomedical Network Research on Rare Diseases

Instituto de Salud Carlos III

International Society for Heart and Lung Transplantation

Charles University

Assistance Publique – Hôpitaux de Paris

University of Hradec Králové

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Vascular pathobiology of pulmonary hypertension

The Journal of Heart and Lung Transplantation (2022)

Eunate Gallardo‐Vara Aglaia Ntokou Jui M. Dave Daniel G. Jovin Fatima Zahra Saddouk

Crosstalk

Mural cell

Cell type

Pathogenesis

Platelet-derived growth factor

10.1016/j.healun.2022.12.012

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Citations (21)

Dedifferentiated early postnatal lung myofibroblasts redifferentiate in adult disease

Frontiers in Cell and Developmental Biology (2024)

Rachana R. Chandran Taylor Adams Inamul Kabir Eunate Gallardo‐Vara Naftali Kaminski

Alveolarization ensures sufficient lung surface area for gas exchange, and during bulk alveolarization in mice (postnatal day [P] 4.5–14.5), alpha-smooth muscle actin (SMA) + myofibroblasts accumulate, secrete elastin, and lay down alveolar septum. Herein, we delineate the dynamics of the lineage of early postnatal SMA + myofibroblasts during and after bulk alveolarization and in response to lung injury. SMA + lung myofibroblasts first appear at ∼ P2.5 and proliferate robustly. Lineage tracing shows that, at P14.5 and over the next few days, the vast majority of SMA + myofibroblasts downregulate smooth muscle cell markers and undergo apoptosis. Of note, ∼8% of these dedifferentiated cells and another ∼1% of SMA + myofibroblasts persist to adulthood. Single cell RNA sequencing analysis of the persistent SMA − cells and SMA + myofibroblasts in the adult lung reveals distinct gene expression profiles. For instance, dedifferentiated SMA − cells exhibit higher levels of tissue remodeling genes. Most interestingly, these dedifferentiated early postnatal myofibroblasts re-express SMA upon exposure of the adult lung to hypoxia or the pro-fibrotic drug bleomycin. However, unlike during alveolarization, these cells that re-express SMA do not proliferate with hypoxia. In sum, dedifferentiated early postnatal myofibroblasts are a previously undescribed cell type in the adult lung and redifferentiate in response to injury.

Myofibroblast

10.3389/fcell.2024.1335061

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Citations (2)

Targeting β2-Adrenergic Receptors Shows Therapeutical Benefits in Clear Cell Renal Cell Carcinoma from Von Hippel–Lindau Disease

Journal of Clinical Medicine (2020)

Virginia Albiñana Eunate Gallardo‐Vara Isabel de Rojas-P Lucía Recio-Poveda Tania Aguado

Von Hippel–Lindau (VHL), is a rare autosomal dominant inherited cancer in which the lack of VHL protein triggers the development of multisystemic tumors such us retinal hemangioblastomas (HB), CNS-HB, and clear cell renal cell carcinoma (ccRCC). ccRCC ranks third in terms of incidence and first in cause of death. Standard systemic therapies for VHL-ccRCC have shown limited response, with recurrent surgeries being the only effective treatment. Targeting of β2-adrenergic receptor (ADRB) has shown therapeutic antitumor benefits on VHL-retinal HB (clinical trial) and VHL-CNS HB (in vitro). Therefore, the in vitro and in vivo antitumor benefits of propranolol (ADRB-1,2 antagonist) and ICI-118,551 (ADRB-2 antagonist) on VHL−/− ccRCC primary cultures and 786-O tumor cell lines have been addressed. Propranolol and ICI-118,551 activated apoptosis inhibited gene and protein expression of HIF-2α, CAIX, and VEGF, and impaired partially the nuclear internalization of HIF-2α and NFĸB/p65. Moreover, propranolol and ICI-118,551 reduced tumor growth on two in vivo xenografts. Finally, ccRCC patients receiving propranolol as off-label treatment have shown a positive therapeutic response for two years on average. In summary, propranolol and ICI-118,551 have shown antitumor benefits in VHL-derived ccRCC, and since ccRCCs comprise 63% of the total RCCs, targeting ADRB2 becomes a promising drug for VHL and other non-VHL tumors.

Von Hippel–Lindau disease

10.3390/jcm9092740

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Citations (13)

Soluble endoglin modulates the pro-inflammatory mediators NF-κB and IL-6 in cultured human endothelial cells

Life Sciences (2017)

Michala Varejckova Eunate Gallardo‐Vara Matej Vicen Barbora Vitverová Petra Fikrová

Endothelial Dysfunction

Endothelial Activation

10.1016/j.lfs.2017.03.014

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Citations (37)

Fatty acids revert the inhibition of respiration caused by the antidiabetic drug metformin to facilitate their mitochondrial β-oxidation

Biochimica et Biophysica Acta (BBA) - Bioenergetics (2012)

M. Mar González‐Barroso Andrea Anedda Eunate Gallardo‐Vara Mariano Redondo‐Horcajo Leonor Rodríguez-Sánchez

Bioenergetics

Cellular respiration

10.1016/j.bbabio.2012.02.019

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Citations (27)

The Role of Propranolol as a Repurposed Drug in Rare Vascular Diseases

International Journal of Molecular Sciences (2022)

Ángel M. Cuesta Eunate Gallardo‐Vara Juan Casado‐Vela Lucía Recio-Poveda Luisa M. Botella

Rare Diseases (RD) are defined by their prevalence in less than 5 in 10,000 of the general population. Considered individually, each RD may seem insignificant, but together they add up to more than 7000 different diseases. Research in RD is not attractive for pharmaceutical companies since it is unlikely to recover development costs for medicines aimed to small numbers of patients. Since most of these diseases are life threatening, this fact underscores the urgent need for treatments. Drug repurposing consists of identifying new uses for approved drugs outside the scope of the original medical indication. It is an alternative option in drug development and represents a viable and risk-managed strategy to develop for RDs. In 2008, the “off label” therapeutic benefits of propranolol were described in the benign tumor Infantile Hemangioma. Propranolol, initially prescribed for high blood pressure, irregular heart rate, essential tremor, and anxiety, has, in the last decade, shown increasing evidence of its antiangiogenic, pro-apoptotic, vasoconstrictor and anti-inflammatory properties in different RDs, including vascular or oncological pathologies. This review highlights the finished and ongoing trials in which propranolol has arisen as a good repurposing drug for improving the health condition in RDs.

10.3390/ijms23084217

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Citations (16)

Endoglin and alk1 as therapeutic targets for hereditary hemorrhagic telangiectasia

Expert Opinion on Therapeutic Targets (2017)

Lı́dia Ruiz Eunate Gallardo‐Vara Elisa Rossi David M. Smadja Luisa M. Botella

Introduction: Hereditary Haemorrhagic Telangiectasia (HHT) is as an autosomal dominant trait characterized by frequent nose bleeds, mucocutaneous telangiectases, arteriovenous malformations (AVMs) of the lung, liver and brain, and gastrointestinal bleedings due to telangiectases. HHT is originated by mutations in genes whose encoded proteins are involved in the transforming growth factor β (TGF-β) family signalling of vascular endothelial cells. In spite of the great advances in the diagnosis as well as in the molecular, cellular and animal models of HHT, the current treatments remain just at the palliative level.Areas covered: Pathogenic mutations in genes coding for the TGF-β receptors endoglin (ENG) (HHT1) or the activin receptor-like kinase-1 (ACVRL1 or ALK1) (HHT2), are responsible for more than 80% of patients with HHT. Therefore, ENG and ALK1 are the main potential therapeutic targets for HHT and the focus of this review. The current status of the preclinical and clinical studies, including the anti-angiogenic strategy, have been addressed.Expert opinion: Endoglin and ALK1 are attractive therapeutic targets in HHT. Because haploinsufficiency is the pathogenic mechanism in HHT, several therapeutic approaches able to enhance protein expression and/or function of endoglin and ALK1 are keys to find novel and efficient treatments for the disease.

Telangiectases

ACVRL1

Haploinsufficiency

10.1080/14728222.2017.1365839

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Citations (89)

Endoglin (CD105) and VEGF as potential angiogenic and dissemination markers for colorectal cancer

World Journal of Surgical Oncology (2020)

Ana Nogués Pevidal Eunate Gallardo‐Vara María Paz Zafra P Maté Jose Luis Marijuan

Abstract Background Colorectal cancer (CRC) is an important current problem concerning public health due to its high incidence and mortality. Advances in molecular and cellular knowledge and the detection of new disease biomarkers are very important to improve prognosis, prediction, and early diagnosis. In this study, we aimed to analyze the gene and protein expression levels of two angiogenic markers, VEGF and soluble Endoglin, during different tumor stages as well as at different stages of cancer treatment, to predict the diagnosis and evolution of colon and rectal cancer. Material and methods This study includes 133 CRC patients (93 with colon cancer and 40 with rectal cancer) on which the gene and protein expression of Endoglin (membrane and soluble form) and VEGF were analyzed by molecular and immunohistochemical techniques on different tumor stage samples and plasma obtained preoperatively as well as 3, 6, and 9 months after resection of the tumor. Results VEGF and Endoglin gene expressions were higher in tumor tissue than in surrounding non-tumoral tissue for both types of cancer. The VEGF levels in plasma were found to decrease in less aggressive tumors, whereas soluble Endoglin was increased in preoperative samples of patients with metastasis. Membrane Endoglin expression was higher on the vascular endothelium of more aggressive tumors. In contrast, Endoglin expression was mainly in the colon epithelium in less aggressive stage tumors. Conclusion Endoglin and VEGF are proteins with a major role in the tumor angiogenesis process. This study performed with a wide cohort of human samples shows that both proteins seem to be valuable biomarkers in the diagnosis and prognosis of CRC.

Surgical oncology

10.1186/s12957-020-01871-2

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Citations (22)

Age of the bone marrow dictates clonality of smooth muscle-derived cells in the atherosclerotic plaque

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Inamul Kabir Xinbo Zhang Jui M. Dave Raja Chakraborty Rihao Qu

SUMMARY Aging is the predominant risk factor for atherosclerosis, the leading cause of death. Rare smooth muscle cell (SMC) progenitors clonally expand giving rise to up to ∼70% of atherosclerotic plaque cells; however, the effect of age on SMC clonality is not known. Our results indicate that aged bone marrow (BM)-derived cells non-cell autonomously induce SMC polyclonality and worsen atherosclerosis. Indeed, in myeloid cells from aged mice and humans, TET2 levels are reduced which epigenetically silences integrin β3 resulting in increased tumor necrosis factor [TNF]-α signaling. In turn, TNFα signals through TNF receptor 1 on SMCs to promote proliferation and induces recruitment and expansion of multiple SMC progenitors into the atherosclerotic plaque. Notably, integrin β3 overexpression in aged BM preserves dominance of the lineage of a single SMC progenitor and attenuates plaque burden. Our results demonstrate a molecular mechanism of aged macrophage-induced SMC polyclonality and atherogenesis and suggest novel therapeutic strategies. Graphical abstract Age of BM-derived monocytes/macrophages determines clonality of SMC lineage in the atherosclerotic plaque. Atherogenesis is depicted in a young ( a ) or aged ( b ) host. Aged monocytes/macrophages have decreased levels of the epigenetic regulator TET2, leading to reduction of the 5-hydroxymethylcytosine (5hmC) mark on the Itgb3 promoter. The resulting low integrin β3 levels in aged monocytes/macrophages induces high TNF-α levels, facilitating recruitment and expansion of multiple SMC progenitors (polyclonality) in the atherosclerotic plaque and worse disease burden. In contrast, the young control is characterized by mono/oligoclonal SMC expansion in a smaller plaque.

Monocyte

Fibrous cap

10.1101/2022.01.18.476756

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Citations (0)

Development of Chromanes as Novel Inhibitors of the Uncoupling Proteins

Chemistry & Biology (2011)

Eduardo Rial Leonor Rodríguez-Sánchez Patricio Aller Arancha Guisado M. Mar González‐Barroso

Arsenic Trioxide

10.1016/j.chembiol.2010.12.012

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Citations (26)