Developmental Regression of Hyaloid Vasculature is Triggered by Neurons

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2016 Jun 22

PMID 27325890

Citations 24

Authors

Yusuke Yoshikawa

Toru Yamada

Ikue Tai-Nagara

Keisuke Okabe

Yuko Kitagawa

Masatsugu Ema

Yoshiaki Kubota

Affiliations

Soon will be listed here.

Abstract

Vascular development involves not only vascular growth, but also regression of transient or unnecessary vessels. Hyaloid vasculature is the temporary circulatory system in fetal eyes, which spontaneously degenerates when the retinal blood vessels start to grow. Failure of the hyaloid vessels to regress leads to disease in humans, persistent hyperplastic primary vitreous, which causes severe intraocular hemorrhage and impairs visual function. However, the mechanism underlying the endogenous program that mediates spontaneous regression of the hyaloid vessels is not well understood. In this study, we identify a robust switch triggering this program directed by neurons in mice. Marked up-regulation of vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) occurs in retinal neurons just after birth via distal-multipotent-mesodermal enhancer, a hemangioblast-specific enhancer of VEGFR2. Genetic deletion of neuronal VEGFR2 interrupts this program, resulting in massive hyaloid vessels that persist even during late postnatal days. This abnormality is caused by excessive VEGF proteins in the vitreous cavity as a result of impairment in the neuronal sequestration of VEGF. Collectively, our data indicate that neurons trigger transition from the fetal to the postnatal circulatory systems in the retina.

Citing Articles

Pediatric retinal vascular disorders: From translational sciences to clinical practice.

Maitra P Saudi J Ophthalmol. 2023; 37(4):269-275.

PMID: 38155677 PMC: 10752273. DOI: 10.4103/sjopt.sjopt_63_23.

Senescent Cells: Dual Implications on the Retinal Vascular System.

Habibi-Kavashkohie M, Scorza T, Oubaha M Cells. 2023; 12(19).

PMID: 37830555 PMC: 10571659. DOI: 10.3390/cells12192341.

Non-typical persistent hyperplastic primary vitreous: a rare case report and review of the literature.

Yu Y, Qiao Y, Chen S, Hu J, Li J, Yao K BMC Ophthalmol. 2023; 23(1):267.

PMID: 37312173 PMC: 10262480. DOI: 10.1186/s12886-023-03024-x.

Single-Cell Characterization of the Frizzled 5 (Fz5) Mutant Mouse and Human Persistent Fetal Vasculature (PFV).

Chen Y, Wu C, Peng S, Guo D, Ouyang H, Wei Y Invest Ophthalmol Vis Sci. 2023; 64(3):8.

PMID: 36867129 PMC: 9988703. DOI: 10.1167/iovs.64.3.8.

Three-dimensional characterization of developing and adult ocular vasculature in mice using in toto clearing.

Darche M, Verschueren A, Belle M, Boucherit L, Fouquet S, Sahel J Commun Biol. 2022; 5(1):1135.

PMID: 36302949 PMC: 9613908. DOI: 10.1038/s42003-022-04104-2.

References

Ishitobi H, Wakamatsu A, Liu F, Azami T, Hamada M, Matsumoto K . Molecular basis for Flk1 expression in hemato-cardiovascular progenitors in the mouse. Development. 2011; 138(24):5357-68. PMC: 4074304. DOI: 10.1242/dev.065565. View

Rattner A, Wang Y, Zhou Y, Williams J, Nathans J . The role of the hypoxia response in shaping retinal vascular development in the absence of Norrin/Frizzled4 signaling. Invest Ophthalmol Vis Sci. 2014; 55(12):8614-25. PMC: 4280883. DOI: 10.1167/iovs.14-15693. View

Usui Y, Westenskow P, Kurihara T, Aguilar E, Sakimoto S, Paris L . Neurovascular crosstalk between interneurons and capillaries is required for vision. J Clin Invest. 2015; 125(6):2335-46. PMC: 4497761. DOI: 10.1172/JCI80297. View

Kubota Y, Takubo K, Shimizu T, Ohno H, Kishi K, Shibuya M . M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis. J Exp Med. 2009; 206(5):1089-102. PMC: 2715025. DOI: 10.1084/jem.20081605. View

Marquardt T, Ashery-Padan R, Andrejewski N, Scardigli R, Guillemot F, Gruss P . Pax6 is required for the multipotent state of retinal progenitor cells. Cell. 2001; 105(1):43-55. DOI: 10.1016/s0092-8674(01)00295-1. View

Wang Y, Rattner A, Zhou Y, Williams J, Smallwood P, Nathans J . Norrin/Frizzled4 signaling in retinal vascular development and blood brain barrier plasticity. Cell. 2012; 151(6):1332-44. PMC: 3535266. DOI: 10.1016/j.cell.2012.10.042. View

Okabe K, Kobayashi S, Yamada T, Kurihara T, Tai-Nagara I, Miyamoto T . Neurons limit angiogenesis by titrating VEGF in retina. Cell. 2014; 159(3):584-96. DOI: 10.1016/j.cell.2014.09.025. View

Albuquerque R, Hayashi T, Cho W, Kleinman M, Dridi S, Takeda A . Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth. Nat Med. 2009; 15(9):1023-30. PMC: 2882165. DOI: 10.1038/nm.2018. View

Sapieha P, Sirinyan M, Hamel D, Zaniolo K, Joyal J, Cho J . The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis. Nat Med. 2008; 14(10):1067-76. DOI: 10.1038/nm.1873. View

10.

Ye X, Wang Y, Nathans J . The Norrin/Frizzled4 signaling pathway in retinal vascular development and disease. Trends Mol Med. 2010; 16(9):417-25. PMC: 2963063. DOI: 10.1016/j.molmed.2010.07.003. View

11.

Ishitobi H, Matsumoto K, Azami T, Itoh F, Itoh S, Takahashi S . Flk1-GFP BAC Tg mice: an animal model for the study of blood vessel development. Exp Anim. 2010; 59(5):615-22. DOI: 10.1538/expanim.59.615. View

12.

Rao S, Chun C, Fan J, Kofron J, Yang M, Hegde R . A direct and melanopsin-dependent fetal light response regulates mouse eye development. Nature. 2013; 494(7436):243-6. PMC: 3746810. DOI: 10.1038/nature11823. View

13.

Muranishi Y, Terada K, Inoue T, Katoh K, Tsujii T, Sanuki R . An essential role for RAX homeoprotein and NOTCH-HES signaling in Otx2 expression in embryonic retinal photoreceptor cell fate determination. J Neurosci. 2011; 31(46):16792-807. PMC: 6633304. DOI: 10.1523/JNEUROSCI.3109-11.2011. View

14.

Kurihara T, Kubota Y, Ozawa Y, Takubo K, Noda K, Simon M . von Hippel-Lindau protein regulates transition from the fetal to the adult circulatory system in retina. Development. 2010; 137(9):1563-71. PMC: 3224975. DOI: 10.1242/dev.049015. View

15.

Lang R, Bishop J . Macrophages are required for cell death and tissue remodeling in the developing mouse eye. Cell. 1993; 74(3):453-62. DOI: 10.1016/0092-8674(93)80047-i. View

16.

Xu Q, Wang Y, Dabdoub A, Smallwood P, Williams J, Woods C . Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Cell. 2004; 116(6):883-95. DOI: 10.1016/s0092-8674(04)00216-8. View

17.

Ambati B, Nozaki M, Singh N, Takeda A, Jani P, Suthar T . Corneal avascularity is due to soluble VEGF receptor-1. Nature. 2006; 443(7114):993-7. PMC: 2656128. DOI: 10.1038/nature05249. View

18.

Gerber H, Hillan K, Ryan A, Kowalski J, Keller G, RANGELL L . VEGF is required for growth and survival in neonatal mice. Development. 1999; 126(6):1149-59. DOI: 10.1242/dev.126.6.1149. View

19.

Potente M, Gerhardt H, Carmeliet P . Basic and therapeutic aspects of angiogenesis. Cell. 2011; 146(6):873-87. DOI: 10.1016/j.cell.2011.08.039. View

20.

Silbert , Gurwood . Persistent hyperplastic primary vitreous. Clin Eye Vis Care. 2001; 12(3-4):131-137. DOI: 10.1016/s0953-4431(00)00054-0. View