气候变化领域集成服务门户(CCPortal): Impaired TRPV4-eNOS signaling in trabecular meshwork elevates intraocular pressure in glaucoma

CCPortal

DOI	10.1073/pnas.2022461118
	Impaired TRPV4-eNOS signaling in trabecular meshwork elevates intraocular pressure in glaucoma
	Patel P.D.; Chen Y.-L.; Kasetti R.B.; Maddineni P.; Mayhew W.; Millar J.C.; Ellis D.Z.; Sonkusare S.K.; Zode G.S.
发表日期	2021
ISSN	00278424
卷号	118 期号:16
英文摘要	Primary Open Angle Glaucoma (POAG) is the most common form of glaucoma that leads to irreversible vision loss. Dysfunction of trabecular meshwork (TM) tissue, a major regulator of aqueous humor (AH) outflow resistance, is associated with intraocular pressure (IOP) elevation in POAG. However, the underlying pathological mechanisms of TM dysfunction in POAG remain elusive. In this regard, transient receptor potential vanilloid 4 (TRPV4) cation channels are known to be important Ca2+ entry pathways in multiple cell types. Here, we provide direct evidence supporting Ca2+ entry through TRPV4 channels in human TM cells and show that TRPV4 channels in TM cells can be activated by increased fluid flow/shear stress. TM-specific TRPV4 channel knockout in mice elevated IOP, supporting a crucial role for TRPV4 channels in IOP regulation. Pharmacological activation of TRPV4 channels in mouse eyes also improved AH outflow facility and lowered IOP. Importantly, TRPV4 channels activated endothelial nitric oxide synthase (eNOS) in TM cells, and loss of eNOS abrogated TRPV4-induced lowering of IOP. Remarkably, TRPV4-eNOS signaling was significantly more pronounced in TM cells compared to Schlemm's canal cells. Furthermore, glaucomatous human TM cells show impaired activity of TRPV4 channels and disrupted TRPV4-eNOS signaling. Flow/shear stress activation of TRPV4 channels and subsequent NO release were also impaired in glaucomatous primary human TM cells. Together, our studies demonstrate a central role for TRPV4-eNOS signaling in IOP regulation. Our results also provide evidence that impaired TRPV4 channel activity in TM cells contributes to TM dysfunction and elevated IOP in glaucoma. © This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
英文关键词	Fluid flow; Glaucoma; Nitric oxide; Trabecular meshwork; TRPV4
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179798
作者单位	Department of Pharmacology and Neuroscience, North Texas Eye Research Institute, University of North Texas, Health Science Center at Fort Worth, Fort Worth, TX 76107, United States; Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, United States; Department of Pharmaceutical Sciences, North Texas Eye Research Institute, University of North Texas, Health Science Center at Fort Worth, Fort Worth, TX 76107, United States; Molecular Physiology and Biological Physics, University of Virginia, School of Medicine, Charlottesville, VA 22908, United States
推荐引用方式 GB/T 7714	Patel P.D.,Chen Y.-L.,Kasetti R.B.,et al. Impaired TRPV4-eNOS signaling in trabecular meshwork elevates intraocular pressure in glaucoma[J],2021,118(16).
APA	Patel P.D..,Chen Y.-L..,Kasetti R.B..,Maddineni P..,Mayhew W..,...&Zode G.S..(2021).Impaired TRPV4-eNOS signaling in trabecular meshwork elevates intraocular pressure in glaucoma.Proceedings of the National Academy of Sciences of the United States of America,118(16).
MLA	Patel P.D.,et al."Impaired TRPV4-eNOS signaling in trabecular meshwork elevates intraocular pressure in glaucoma".Proceedings of the National Academy of Sciences of the United States of America 118.16(2021).