Next Article in Journal
cGMP Signaling and Vascular Smooth Muscle Cell Plasticity
Previous Article in Journal
The Popeye Domain Containing Genes and Their Function as cAMP Effector Proteins in Striated Muscle
Article Menu

Export Article

Open AccessFeature PaperArticle
J. Cardiovasc. Dev. Dis. 2018, 5(2), 19; doi:10.3390/jcdd5020019

Hypoxia Supports Epicardial Cell Differentiation in Vascular Smooth Muscle Cells through the Activation of the TGFβ Pathway

1
Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
2
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
3
Department of Pediatrics, Rainbow Babies and Children’s Hospital, The Congenital Heart Collaborative, Cleveland, OH 44106, USA
4
University Hospitals Harrington-McLaughlin Heart & Vascular Institute, Cleveland, OH 44106, USA
Current affiliation: Department of Physicians Assistants, University of Toledo, Toledo, OH 43614, USA.
*
Author to whom correspondence should be addressed.
Received: 16 January 2018 / Revised: 4 April 2018 / Accepted: 4 April 2018 / Published: 13 April 2018
View Full-Text   |   Download PDF [5624 KB, uploaded 13 April 2018]   |  

Abstract

Epicardium-derived cells (EPDCs) are an important pool of multipotent cardiovascular progenitor cells. Through epithelial-to-mesenchymal-transition (EMT), EPDCs invade the subepicardium and myocardium and further differentiate into several cell types required for coronary vessel formation. We previously showed that epicardial hypoxia inducible factor (HIF) signaling mediates the invasion of vascular precursor cells critical for patterning the coronary vasculature. Here, we examine the regulatory role of hypoxia (1% oxygen) on EPDC differentiation into vascular smooth muscle cells (VSMCs). Results: Hypoxia stimulates EMT and enhances expression of several VSMC markers in mouse epicardial cell cultures. This stimulation is specifically blocked by inhibiting transforming growth factor-beta (TGFβ) receptor I. Further analyses indicated that hypoxia increases the expression level of TGFβ-1 ligand and phosphorylation of TGFβ receptor II, suggesting an indispensable role of the TGFβ pathway in hypoxia-stimulated VSMC differentiation. We further demonstrate that the non-canonical RhoA/Rho kinase (ROCK) pathway acts as the main downstream effector of TGFβ to modulate hypoxia’s effect on VSMC differentiation. Conclusion: Our results reveal a novel role of epicardial HIF in mediating coronary vasculogenesis by promoting their differentiation into VSMCs through noncanonical TGFβ signaling. These data elucidate that patterning of the coronary vasculature is influenced by epicardial hypoxic signals. View Full-Text
Keywords: hypoxia inducible factor; hypoxia; transforming growth factor beta; TGFβ; RhoA/ROCK; epicardial cell; epithelial-to-mesenchymal-transition; vascular smooth muscle cells; coronary vasculature hypoxia inducible factor; hypoxia; transforming growth factor beta; TGFβ; RhoA/ROCK; epicardial cell; epithelial-to-mesenchymal-transition; vascular smooth muscle cells; coronary vasculature
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Share & Cite This Article

MDPI and ACS Style

Tao, J.; Barnett, J.V.; Watanabe, M.; Ramírez-Bergeron, D. Hypoxia Supports Epicardial Cell Differentiation in Vascular Smooth Muscle Cells through the Activation of the TGFβ Pathway. J. Cardiovasc. Dev. Dis. 2018, 5, 19.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
J. Cardiovasc. Dev. Dis. EISSN 2308-3425 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top