Age-Related Decline of Autocrine Pituitary Adenylate Cyclase-Activating Polypeptide Impairs Angiogenic Capacity of Rat Cerebromicrovascular Endothelial Cells

Eszter Banki, Danuta Sosnowska, Zsuzsanna Tucsek, Tripti Gautam, Peter Toth, Stefano Tarantini, A. Tamás, Z. Helyes, D. Reglodi, William E. Sonntag, Anna Csiszar, Zoltan Ungvari

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)665-674
Number of pages10
JournalJournals of Gerontology - Series A Biological Sciences and Medical Sciences
Volume70
Issue number6
DOIs
Publication statusPublished - 2015

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Pituitary Adenylate Cyclase-Activating Polypeptide
Endothelial Cells
Autocrine Communication
Apoptosis
Adhesiveness
Cell Aging
Neuropeptides
Electric Impedance
Cell Adhesion
Small Interfering RNA
Reactive Oxygen Species
Collagen
Fluorescence
Technology
Phenotype
Neurons

Keywords

  • Capillary density
  • Ischemia
  • Senescence
  • Vascular cognitive impairment
  • Vasculardementia

ASJC Scopus subject areas

  • Ageing
  • Geriatrics and Gerontology

Cite this

Age-Related Decline of Autocrine Pituitary Adenylate Cyclase-Activating Polypeptide Impairs Angiogenic Capacity of Rat Cerebromicrovascular Endothelial Cells. / Banki, Eszter; Sosnowska, Danuta; Tucsek, Zsuzsanna; Gautam, Tripti; Toth, Peter; Tarantini, Stefano; Tamás, A.; Helyes, Z.; Reglodi, D.; Sonntag, William E.; Csiszar, Anna; Ungvari, Zoltan.

In: Journals of Gerontology - Series A Biological Sciences and Medical Sciences, Vol. 70, No. 6, 2015, p. 665-674.

Research output: Contribution to journalArticle

Banki, Eszter ; Sosnowska, Danuta ; Tucsek, Zsuzsanna ; Gautam, Tripti ; Toth, Peter ; Tarantini, Stefano ; Tamás, A. ; Helyes, Z. ; Reglodi, D. ; Sonntag, William E. ; Csiszar, Anna ; Ungvari, Zoltan. / Age-Related Decline of Autocrine Pituitary Adenylate Cyclase-Activating Polypeptide Impairs Angiogenic Capacity of Rat Cerebromicrovascular Endothelial Cells. In: Journals of Gerontology - Series A Biological Sciences and Medical Sciences. 2015 ; Vol. 70, No. 6. pp. 665-674.
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AU - Tucsek, Zsuzsanna

AU - Gautam, Tripti

AU - Toth, Peter

AU - Tarantini, Stefano

AU - Tamás, A.

AU - Helyes, Z.

AU - Reglodi, D.

AU - Sonntag, William E.

AU - Csiszar, Anna

AU - Ungvari, Zoltan

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AB - 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.

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