title: Age-related decline of autocrine pituitary adenylate cyclase-activating polypeptide impairs angiogenic capacity of rat cerebromicrovascular endothelial cells.
abstract: Aging impairs angiogenic capacity of cerebromicrovascular endothelial cells (CMVECs) promoting microvascular rarefaction, but the underlying mechanisms remain elusive. PACAP is an evolutionarily conserved neuropeptide secreted by endothelial cells and neurons, which confers important antiaging effects. To test the hypothesis that age-related changes in autocrine PACAP signaling contributes to dysregulation of endothelial angiogenic capacity, primary CMVECs were isolated from 3-month-old (young) and 24-month-old (aged) Fischer 344 x Brown Norway rats. In aged CMVECs, expression of PACAP was decreased, which was associated with impaired capacity to form capillary-like structures, impaired adhesiveness to collagen (assessed using electric cell-substrate impedance sensing [ECIS] technology), and increased apoptosis (caspase3 activity) when compared with young cells. Overexpression of PACAP in aged CMVECs resulted in increased formation of capillary-like structures, whereas it did not affect cell adhesion. Treatment with recombinant PACAP also significantly increased endothelial tube formation and inhibited apoptosis in aged CMVECs. In young CMVECs shRNA knockdown of autocrine PACAP expression significantly impaired tube formation capacity, mimicking the aging phenotype. Cellular and mitochondrial reactive oxygen species production (dihydroethidium and MitoSox fluorescence, respectively) were increased in aged CMVECs and were unaffected by PACAP. Collectively, PACAP exerts proangiogenic effects and age-related dysregulation of autocrine PACAP signaling may contribute to impaired angiogenic capacity of CMVECs in aging.
authors.affiliation: Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center. Department of Anatomy, MTA-PTE PACAP Lendulet Research Team.
authors.forename: Eszter
authors.initials: E
authors.lastname: Banki
authors.affiliation: Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center.
authors.forename: Danuta
authors.initials: D
authors.lastname: Sosnowska
authors.affiliation: Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Tucsek
authors.affiliation: Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center.
authors.forename: Tripti
authors.initials: T
authors.lastname: Gautam
authors.affiliation: Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center.
authors.forename: Peter
authors.initials: P
authors.lastname: Toth
authors.affiliation: Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center.
authors.forename: Stefano
authors.initials: S
authors.lastname: Tarantini
authors.affiliation: Department of Anatomy, MTA-PTE PACAP Lendulet Research Team.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tamas
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Szentágothai Research Center, and.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Helyes
authors.affiliation: Department of Anatomy, MTA-PTE PACAP Lendulet Research Team.
authors.forename: Dora
authors.initials: D
authors.lastname: Reglodi
authors.affiliation: Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center.
authors.forename: William E
authors.initials: WE
authors.lastname: Sonntag
authors.affiliation: Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center. Department of Pathophysiology and Gerontology, Medical School and Szentagothai Research Center, University of Pécs, Hungary. Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center.
authors.forename: Anna
authors.initials: A
authors.lastname: Csiszar
authors.affiliation: Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center. Department of Pathophysiology and Gerontology, Medical School and Szentagothai Research Center, University of Pécs, Hungary. Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center. zoltan-ungvari@ouhsc.edu.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Ungvari
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000098:blood supply*; D053148:Caspase 3 / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D055785:Gene Knockdown Techniques; D018919:Neovascularization, Physiologic; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D040301:Vascular Endothelial Growth Factor Receptor-2; D053148:Caspase 3
keywords: Capillary density; Ischemia; Senescence; Vascular cognitive impairment; Vasculardementia