title: Senescence-associated secretory phenotype contributes to pathological angiogenesis in retinopathy.
abstract: Pathological angiogenesis is the hallmark of diseases such as cancer and retinopathies. Although tissue hypoxia and inflammation are recognized as central drivers of vessel growth, relatively little is known about the process that bridges the two. In a mouse model of ischemic retinopathy, we found that hypoxic regions of the retina showed only modest rates of apoptosis despite severely compromised metabolic supply. Using transcriptomic analysis and inducible loss-of-function genetics, we demonstrated that ischemic retinal cells instead engage the endoplasmic reticulum stress inositol-requiring enzyme 1α (IRE1α) pathway that, through its endoribonuclease activity, induces a state of senescence in which cells adopt a senescence-associated secretory phenotype (SASP). We also detected SASP-associated cytokines (plasminogen activator inhibitor 1, interleukin-6, interleukin-8, and vascular endothelial growth factor) in the vitreous humor of patients suffering from proliferative diabetic retinopathy. Therapeutic inhibition of the SASP through intravitreal delivery of metformin or interference with effectors of senescence (semaphorin 3A or IRE1α) in mice reduced destructive retinal neovascularization in vivo. We conclude that the SASP contributes to pathological vessel growth, with ischemic retinal cells becoming prematurely senescent and secreting inflammatory cytokines that drive paracrine senescence, exacerbate destructive angiogenesis, and hinder reparative vascular regeneration. Reversal of this process may be therapeutically beneficial.
authors: Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada.|Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 2B4 Canada.
authors: Malika
authors: M
authors: Oubaha
authors: Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 2B4 Canada.
authors: Khalil
authors: K
authors: Miloudi
authors: Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada.
authors: Agnieszka
authors: A
authors: Dejda
authors: Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada.
authors: Vera
authors: V
authors: Guber
authors: Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada.
authors: Gaëlle
authors: G
authors: Mawambo
authors: Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada.|Department of Medicine, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada.
authors: Marie-Anne
authors: MA
authors: Germain
authors: Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada.
authors: Guillaume
authors: G
authors: Bourdel
authors: Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada.
authors: Natalija
authors: N
authors: Popovic
authors: Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada.
authors: Flavio A
authors: FA
authors: Rezende
authors: Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors: Randal J
authors: RJ
authors: Kaufman
authors: Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada. mike.sapieha@umontreal.ca fa.mallette@umontreal.ca.|Department of Medicine, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada.
authors: Frédérick A
authors: FA
authors: Mallette
authors: Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada. mike.sapieha@umontreal.ca fa.mallette@umontreal.ca.|Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 2B4 Canada.|Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada.
authors: Przemyslaw
authors: P
authors: Sapieha
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D016207:Cytokines / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000097:blood* / Q000503:physiopathology; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D010100:Oxygen / Q000737:chemistry; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012160:Retina / Q000473:pathology; D015861:Retinal Neovascularization; D012171:Retinal Vessels / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014821:Vitrectomy
chemical_list: D016207:Cytokines; D042461:Vascular Endothelial Growth Factor A; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D010100:Oxygen