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缺氧可能通过VEGF-R2和SOX17介导的信号通路调节冠状动脉的发育性血管生成。

Hypoxia regulate developmental coronary angiogenesis potentially through VEGF-R2- and SOX17-mediated signaling.

作者信息

Vitali Halie E, Kuschel Bryce, Sherpa Chhiring, Jones Brendan W, Jacob Nisha, Madiha Syeda A, Elliott Sam, Dziennik Eddie, Kreun Lily, Conatser Cora, Bhetwal Bhupal P, Sharma Bikram

机构信息

Department of Biology, Ball State University, Muncie, Indiana, USA.

Department of Medical Sciences, Hackensack Meridian School of Medicine, Nutley, New Jersey, USA.

出版信息

Dev Dyn. 2025 Feb;254(2):174-188. doi: 10.1002/dvdy.750. Epub 2024 Oct 3.

DOI:10.1002/dvdy.750
PMID:39360476
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11810610/
Abstract

BACKGROUND

The development of coronary vessels in embryonic mouse heart involves various progenitor populations, including sinus venosus (SV), endocardium, and proepicardium. ELA/APJ signaling is known to regulate coronary growth from the SV, whereas VEGF-A/VEGF-R2 signaling controls growth from the endocardium. Previous studies suggest hypoxia might regulate coronary growth, but its specific downstream pathways are unclear. In this study, we further investigated the role of hypoxia and have identified SOX17- and VEGF-R2-mediated signaling as the potential downstream pathways in its regulation of developmental coronary angiogenesis.

RESULTS

HIF-1α stabilization by knocking out von Hippel Lindau (VHL) protein in the myocardium (cKO) disrupted normal coronary angiogenesis in embryonic mouse hearts, resembling patterns of accelerated coronary growth. VEGF-R2 expression was increased in coronary endothelial cells under hypoxia in vitro and in VHL cKO hearts in vivo. Similarly, SOX17 expression was increased in the VHL cKO hearts, while its knockout in the endocardium disrupted normal coronary growth.

CONCLUSION

These findings provide further evidence that hypoxia regulates developmental coronary growth potentially through VEGF-R2 and SOX17 pathways, shedding light on mechanisms of coronary vessel development.

摘要

背景

胚胎期小鼠心脏中冠状动脉的发育涉及多种祖细胞群体，包括静脉窦（SV）、心内膜和心外膜。已知ELA/APJ信号通路调节来自静脉窦的冠状动脉生长，而VEGF-A/VEGF-R2信号通路控制来自心内膜的生长。先前的研究表明缺氧可能调节冠状动脉生长，但其具体的下游通路尚不清楚。在本研究中，我们进一步研究了缺氧的作用，并确定SOX17和VEGF-R2介导的信号通路是其调节发育性冠状动脉血管生成的潜在下游通路。

结果

通过敲除心肌中的冯·希佩尔·林道（VHL）蛋白（cKO）使HIF-1α稳定，破坏了胚胎期小鼠心脏中正常的冠状动脉血管生成，类似于冠状动脉加速生长的模式。体外缺氧条件下以及体内VHL cKO心脏的冠状动脉内皮细胞中VEGF-R2表达增加。同样，VHL cKO心脏中SOX17表达增加，而在心内膜中敲除SOX17会破坏正常的冠状动脉生长。

结论

这些发现进一步证明缺氧可能通过VEGF-R2和SOX17通路调节发育性冠状动脉生长，为冠状动脉血管发育机制提供了新的线索。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93cf/11810610/5b8f7c091b7a/nihms-2027514-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93cf/11810610/e8c793c4c99d/nihms-2027514-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93cf/11810610/33e793821598/nihms-2027514-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93cf/11810610/60b0d1238207/nihms-2027514-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93cf/11810610/27135310420d/nihms-2027514-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93cf/11810610/904dcfefefe7/nihms-2027514-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93cf/11810610/5b8f7c091b7a/nihms-2027514-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93cf/11810610/e8c793c4c99d/nihms-2027514-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93cf/11810610/33e793821598/nihms-2027514-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93cf/11810610/60b0d1238207/nihms-2027514-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93cf/11810610/27135310420d/nihms-2027514-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93cf/11810610/904dcfefefe7/nihms-2027514-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93cf/11810610/5b8f7c091b7a/nihms-2027514-f0006.jpg

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