Cellular and molecular responses to hypoxia

Hypoxia plays critical functional roles in the pathophysiology of numerous diseases, including cancer and chronic lung diseases, which are responsible for 60% of deaths worldwide. Understanding how cells perceive and respond to changes in oxygen availability and the physiological and pathological consequences in the context of chronic diseases will have a positive impact on the diagnosis and treatment of such pathologies. The group is currently investigating the role of hypoxia in the regulation of extracellular matrix protein thrombospondin-1 (THBS1) in the context of pulmonary hypertension and renal carcinoma.

Pulmonary arterial hypertension (PAH) is a rapidly progressive vascular disease with multifactorial aetiopathogenesis resulting in right-sided heart failure and death. Oxidative stress is a key event in the pathogenesis of PAH, although the mechanisms involved are not fully known. Previous group results showed that the extracellular matrix protein thrombospondin-1 (THBS1) increases in the lungs of subjects with PAH, while mice lacking THBS1 are protected against hypoxia-mediated PAH. In addition, THBS1 activation of the CD47 receptor is increased in experimental and human PAH, and promotes disease by limiting Cav-1 inhibition of dysregulated eNOS.

Our recent studies provide more knowledge about the mechanisms by which THBS1 is regulated in hypoxic lungs, and how this contributes to PAH. Preliminary studies in animal models and human samples from patients with PAH demonstrate that HIF2α is necessary for increased THBS1 in hypoxia-mediated lungs. Additionally, in vitro and ex vivo studies reveal that THBS1 contributes to vascular remodelling by inducing cell migration and regulating hypoxic pulmonary arterial contractility, both characteristics of PAH. These results point to THBS1 as a causal molecule in clinical and experimental PAH, therefore making it a candidate for therapeutic targeting. We are currently investigating the unexpected role of THBS1 in the regulation of potassium channels, and how this contributes to the accumulation of intracellular calcium that takes place during cell depolarisation prior to vascular contraction. Our future goals seek to explore the role of THBS1 in the inflammatory process during PAH.

Additionally, since THBS1 has been found to be increased in several lung diseases associated with excessive fibrosis, our results probably have implications beyond PAH, therefore the role of THBS-1 in other lung diseases will be explored. We are currently collaborating with international groups at the University of Pittsburgh on a project directly related to our interest in lung diseases (NIH-RO1 2011-2015 and Renewal (2016-2021) under assessment).

Team members

area1-Linea-2_G8_Dra-CalzadaGroup leader:

María Josefa Calzada García

Universidad Autónoma de Madrid – Hospital Universitario de La Princesa

  Other team members:

  • Cintia Fernández Pérez. Hospital Universitario de La Princesa.
  • Javier Sevilla Montero.Universidad Autónoma de Madrid.

Calzada García, María José. Thrombospondin-1 and pulmonary arterial hypertension: TSP1 role in artery muscularization and right ventricle hypertrophy. Proyectos de Cooperación Interuniversitaria UAM – Banco Santander con Estados Unidos. 2017-2019.

Calzada García, María Josefa. Estudio de nuevas dianas terapéuticas en la hipertensión pulmonar. Contribución del nexo TSP1/CD47 en las propiedades estructurales y funcionales de la arteria pulmonar en modelos de ratón. PI13/01866. ISCIII. 2014-2016.

Estudiar los mecanismos mediante los cuales, la hipoxia, a través de la regulación del nexo TSP1/CD47, induce cascadas de señalización que promueven la proliferación, migración y diferenciación de las células que componen la pared arterial pulmonar, afectando a su capacidad contráctil y de transporte.

Esta ayuda está financiada por el Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 y el ISCIII – Subdirección General de Evaluación y Fomento de la Investigación – y cofinanciadas por el FEDER, Programa Operativo de Economía Basada en el Conocimiento (2007‐2013) de acuerdo con el Reglamento (CE) nº 1083/2006 del Consejo de 11 de julio de 2006.


Calzada García, María Josefa. TSP1-CD47 in Promotion of PAH-Associated Vasoconstriction and Vascular Overgrowth. PA10-067. NIH. 2011-2015.

Bauer PM, Bauer EM, Rogers NM, Yao M, Feijoo-Cuaresma M, Pilewski JM, Champion HC, Zuckerbraun BS, Calzada MJ, Isenberg JS. Activated CD47 promotes pulmonary arterial hypertension through targeting caveolin-1. Cardiovasc Res 2012. 93: 682-693. FI: 5.940(Q1). PMID: 22215724. DOI: 10.1093/cvr/cvr356.

Fernández-Sánchez R, Berzal S, Sánchez-Niño MD, Neria F, Gonçalves S, Calabia O, Tejedor A, Calzada MJ, Caramelo C, Deudero JJ, Ortiz A. AG490 promotes HIF-1a accumulation by inhibiting its hydroxylation. Curr. Med. Chem. 2012. 19: 4014-4023. FI: 4.070(Q1). PMID: 22709000.

Fernández-Barral A, Orgaz JL, Gomez V, del Peso L, Calzada MJ, Jiménez B. Hypoxia Negatively Regulates Antimetastatic PEDF in Melanoma Cells by a Hypoxia Inducible Factor-Independent, Autophagy Dependent Mechanism. PLoS One 2012. . FI: 3.730(Q1). PMID: 22457728. DOI: 10.1371/journal.pone.0032989.

Bienes-Martinez, Raquel, Ordonez, Angel, Feijoo-Cuaresma, Monica, Corral-Escariz, Maria, Mateo, Gloria, Stenina, Olga, Jimenez, Benilde, Calzada, Maria J. Autocrine stimulation of clear-cell renal carcinoma cell migration in hypoxia via HIF-independent suppression of thrombospondin-1. Sci Rep 2012. 2: 788-0. FI: 2.927(Q1). PMID: 23145312. DOI: 10.1038/srep00788.