Mechanisms of HIF-2 dependent cellular proliferation in type I cells of the carotid body

• Grant number: 18/20083-1
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: December 10, 2018
• End date: December 09, 2019
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Marilia Cerqueira Leite Seelaender
• Grantee: Joanna Darck Carola Correia Lima
• Supervisor: Peter Jonh Ratcliffe
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of Oxford, England
• Associated to the scholarship: 16/02780-1 - Molecular analysis in the tumor microenvironment of cachectic patients: A search of markers for early diagnosis of the syndrome, BP.DR

Abstract

Hypoxia induces dramatic proliferation of type I carotid body cells (Fielding, 2018; Hoodson, 2016, Macias, 2018). Studies made with CRE-Lox animals provided evidence that HIF-2 but not HIF-1-mediated signaling is necessary for this process (Hodson et al., 2016). Hodson, et al (2016) showed that inducible inactivation of HIF2± could decreases the ventilatory sensitivity after chronic hypoxic exposure. These findings demonstrated by Ratcliffe's group, play important role for PHD2 and HIF2± in carotid body biology and manifest several features that are reminiscent of human paraganglioma. Moreover, Fielding (2018) recently shown the hyperplasia in CB mediate by Type I cell restricted PHD2 inactivation, also manifest the important proliferation of endothelial cells and the vascular compartment. This study failed in observe the process of the trans-differentiation of Type I cells and endothelial cellsrecently showed that Type I cells in the carotid body are the principle proliferating population in response to hypoxia. In addition, the inactivation of HIF-2, specifically in Type I cells, is necessary for proliferation, as well as in the endothelial cells. Considering this fact, which could be the possible specific HIF-2 transcriptional targets? For start to elucidate this question, Fielding et all shown higher levels of VEGF mRNA in Type I cells. These results could be related to the hypothesis that paracrine signals of Type I cells drive expansion of the CB vasculature. High expression of VEGFA was related to angiogenesis, proliferations and epithelial-mesenchymal transition (Lee,2015). Objective: The aim of this internship is to analyse whether VEGFA is the effector signaling molecule in the HIF-2alpha elicited pathway in response to hypoxia.Study Design: To employ the PHD2f/f;VEGFf/f;THCre mice to analyse hypoxia/PHD2 dependent phenotypes in the carotid body as compared to PHD2f/f;THCre mice and wide type mouse. In addition, would seek to investigate the contribution of VEGFAf/f;THCre in chronic hypoxia: Does this mimic HIF-2f/f;RosaCreER (Fielding's previous results) in abolishing ventilatory acclimatization and carotid body proliferation?

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

ECKARDT, LUISE; PRANGE-BARCZYNSKA, MARIA; HODSON, EMMA J.; FIELDING, JAMES W.; CHENG, XIAOTONG; LIMA, JOANNA D. C. C.; KURLEKAR, SAMVID; DOUGLAS, GILLIAN; RATCLIFFE, PETER J.; BISHOP, TAMMIE. evelopmental role of PHD2 in the pathogenesis of pseudohypoxic pheochromocytom. Endocrine-Related Cancer, v. 28, n. 12, p. 757-772, DEC 1 2021. (18/20083-1)

CHENG, XIAOTONG; PRANGE-BARCZYNSKA, MARIA; FIELDING, JAMES W.; ZHANG, MINGHAO; BURRELL, ALANA L.; LIMA, JOANNA DCC; ECKARDT, LUISE; LA ARGLES, ISOBEL; PUGH, CHRISTOPHER W.; BUCKLER, KEITH J.; et al. Marked and rapid effects of pharmacological HIF-2 alpha antagonism on hypoxic ventilatory control. Journal of Clinical Investigation, v. 130, n. 5, p. 15-pg., 2020-05-01. (18/20083-1)