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Retinal Neurons Govern Angiogenesis ...

Joyal, Jean-Sebastien.

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Retinal Neurons Govern Angiogenesis by Regulating Opposing Actions of Semaphorin 3A and Nuclear Protease-Activated Receptor 2.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Retinal Neurons Govern Angiogenesis by Regulating Opposing Actions of Semaphorin 3A and Nuclear Protease-Activated Receptor 2./
Author:	Joyal, Jean-Sebastien.
Description:	236 p.
Notes:	Source: Dissertation Abstracts International, Volume: 74-01(E), Section: B.
Contained By:	Dissertation Abstracts International74-01B(E).
Subject:	Physiology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=NR78782
ISBN:	9780494787823

Retinal Neurons Govern Angiogenesis by Regulating Opposing Actions of Semaphorin 3A and Nuclear Protease-Activated Receptor 2.
Joyal, Jean-Sebastien.

Retinal Neurons Govern Angiogenesis by Regulating Opposing Actions of Semaphorin 3A and Nuclear Protease-Activated Receptor 2. - 236 p.

Source: Dissertation Abstracts International, Volume: 74-01(E), Section: B.

Thesis (Ph.D.)--McGill University (Canada), 2012.

Proliferative retinopathies (PRs), such as proliferative diabetic retinopathy and retinopathy of prematurity, are leading causes of blindness in children and working age adults. PRs are characterized by initial microvascular degeneration, followed by a compensatory albeit pathological hyper-vascularization mounted by the hypoxic retina attempting to reinstate metabolic equilibrium. Paradoxically, this secondary revascularization fails to grow into the most ischemic regions of the retina. Instead, the new vessels are misdirected towards the vitreous, suggesting that vaso-repulsive forces operate in the avascular hypoxic retina. Here we demonstrate that the neuronal guidance cue Semaphorin3A (Sema3A) secreted by severely hypoxic neurons participates in hindering revascularization of ischemic zones within the retina by deviating vessels away from these avascular areas. Using a rodent model of oxygen induced retinopathy, we provide evidence that Sema3A produced by ischemic retinal ganglion neurons contributes to microvascular decay and later forms a chemical barrier that impedes normal revascularization by repelling neo-vessel towards the vitreous. Conversely, silencing Sema3A expression enhances normal vascular regeneration within the ischemic retina, thereby preserving retinal neuronal function, and consequently diminishing aberrant neovascularization.

ISBN: 9780494787823Subjects--Topical Terms:

518431
Physiology.

Retinal Neurons Govern Angiogenesis by Regulating Opposing Actions of Semaphorin 3A and Nuclear Protease-Activated Receptor 2.
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100 1 $a Joyal, Jean-Sebastien. $3 3193233
245 1 0 $a Retinal Neurons Govern Angiogenesis by Regulating Opposing Actions of Semaphorin 3A and Nuclear Protease-Activated Receptor 2.
300 $a 236 p.
500 $a Source: Dissertation Abstracts International, Volume: 74-01(E), Section: B.
500 $a Adviser: Sylvain Chemtob.
502 $a Thesis (Ph.D.)--McGill University (Canada), 2012.
520 $a Proliferative retinopathies (PRs), such as proliferative diabetic retinopathy and retinopathy of prematurity, are leading causes of blindness in children and working age adults. PRs are characterized by initial microvascular degeneration, followed by a compensatory albeit pathological hyper-vascularization mounted by the hypoxic retina attempting to reinstate metabolic equilibrium. Paradoxically, this secondary revascularization fails to grow into the most ischemic regions of the retina. Instead, the new vessels are misdirected towards the vitreous, suggesting that vaso-repulsive forces operate in the avascular hypoxic retina. Here we demonstrate that the neuronal guidance cue Semaphorin3A (Sema3A) secreted by severely hypoxic neurons participates in hindering revascularization of ischemic zones within the retina by deviating vessels away from these avascular areas. Using a rodent model of oxygen induced retinopathy, we provide evidence that Sema3A produced by ischemic retinal ganglion neurons contributes to microvascular decay and later forms a chemical barrier that impedes normal revascularization by repelling neo-vessel towards the vitreous. Conversely, silencing Sema3A expression enhances normal vascular regeneration within the ischemic retina, thereby preserving retinal neuronal function, and consequently diminishing aberrant neovascularization.
520 $a Protease-activated receptor 2 (PAR2) partakes in retinal angiogenesis and was found to inhibit the production of Sema3A in ischemic retinal ganglion cells (RGCs). In light of the newly recognized contribution of RGCs in regulating retinal angiogenesis, we studied the expression and function of PAR2 in these neurons. Interestingly, we detected PAR2 at the cell nucleus of RGCs. To date, many G-protein coupled receptors (GPCRs), like PAR2, have been reported at the cell nucleus where they evoke in situ gene induction. However, the sub-cellular origin of nuclear GPCRs, the mechanisms governing this localization and their nuclear function, as well as the in vivo physiologic manifestation of nuclear GPCRs are not known. We show that PAR2 translocates from the plasma membrane to the nucleus, requiring specific receptor domains (C-terminus and nuclear localization signals) as well as the recruitment of Importin-beta1 and Sorting nexin 11 (SNX11), which interact with microtubules. In turn, nuclear PAR2 recruits transcription factor Sp1 to trigger angiogenic genes and ensued neovascularization. This is the first demonstration of the in vivo physiologic manifestation governed by the nuclear localization of a GPCR. The sub-cellular localization and function of a receptor should therefore be considered in order to achieve more selective therapeutic goals. Approaches that foster normal retinal revascularization and in turn counter pathological neovascularization could prevent or delay the onset of blindness in patients afflicted with ischemic proliferative retinopathies.
520 $a Key words: Angiogenesis, retinopathy of prematurity, semaphorin 3A, VEGF, Protease-activated receptor 2, G-protein coupled receptors, nuclear translocation, sorting nexin 11, importin-beta1, microtubules, nucleus.
590 $a School code: 0781.
650 4 $a Physiology. $3 518431
650 4 $a Neurobiology. $3 588707
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710 2 $a McGill University (Canada). $b Department of Pharmacology & Therapeutics. $3 3193234
773 0 $t Dissertation Abstracts International $g 74-01B(E).
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791 $a Ph.D.
792 $a 2012
793 $a English
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