Sox17 controls emergence and remodeling of Nestin-expressing coronary vessels

Abstract

Rationale: The molecular mechanisms underlying the formation of coronary arteries during development and during cardiac neovascularization after injury are poorly understood. However, a detailed description of the relevant signaling pathways and functional transcription factors regulating these processes is still incomplete. Objective: The goal of this study is to identify novel cardiac transcriptional mechanisms of coronary angiogenesis and vessel remodeling by defining the molecular signatures of coronary vascular endothelial cells (EC) during these complex processes. Methods and Results: We demonstrate that Nes-gfp and Nes-CreERT2 transgenic mouse lines are novel tools for studying the emergence of coronary endothelium and targeting sprouting coronary vessels (but not ventricular endocardium) during development. Furthermore, we identify Sox17 as a critical transcription factor upregulated during the sprouting and remodeling of coronary vessels, visualized by a specific neural enhancer from the Nestin gene that is strongly induced in developing arterioles. Functionally, genetic inducible endothelial deletion of Sox17 causes deficient cardiac remodeling of coronary vessels, resulting in improper coronary artery formation. Conclusions: We demonstrated that Sox17 transcription factor regulates the transcriptional activation of Nestin's enhancer in developing coronary vessels while its genetic deletion leads to inadequate coronary artery formation. These findings identify Sox17 as a critical regulator for the remodeling of coronary vessels in the developing heart.

This work was supported by grants from the Spanish Ministerio de Economía y Competitividad (BFU2012-35892 and Ramón y Cajal Program grant RYC-2011-09209 to J.I.), and FPIMINECO13 fellowship (BES-2013-065514) to S.G.H. Additionally, S.M.-F laboratory received funding from Plan Nacional grant SAF-2011-30308, Ramón y Cajal Program grant RYC-2009-04703, Spanish Cell Therapy Network TerCel, Marie Curie Career Integration Program grant FP7-PEOPLE-2011-RG-294096, ConSEPOC-Comunidad de Madrid grant S2010/BMD-2542 and Howard Hughes International Early Career Scientist grant. This study was also supported by Intramural grants from the Severo Ochoa program (IGP-SO), Fundació La Marató de TV3 (120/C/2015-20153032), and grant RTI2018-095497-B-I00 from MCIU to A.H.; and to MINECO RTI2018-096068, AFM, MDA, LaCaixa-HR17-00040, UPGRADE-H2020-825825 grants and ERC Advanced Grant-741538 to PMC. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). The UPF is a María de Maeztu Unit of Excellence (MDM-2014-0370).