Reduced wall compliance suppresses Akt-dependent apoptosis protection stimulated by pulse perfusion

Manxiang Li, Kuan Rau Chiou, Artem Bugayenko, Kaikobad Irani, David A. Kass

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Reduced arterial compliance and increased pulse pressure are common and major risk factors for cardiovascular disease. Here, we reveal a novel mechanism whereby loss of wall distensibility blunts endothelial cell protection to oxidant stress-induced apoptosis. Bovine aortic endothelial cells cultured in compliant or stiff silastic tubes were pulse perfused by arterial pressure/flow waveforms generated by a servo-pump. Pulse perfusion induced time-dependent Akt activation peaking >6-fold after 2 hours in compliant tubes and a similar time course but half the magnitude in stiff tubes. This was accompanied by quantitatively similar disparities in phosphoinositide-3 kinase activation and in Akt-stimulated suppressors of apoptosis: glycogen synthase kinase-3β, forkhead, and Bad. Cells perfused in compliant tubes had twice the protection against H2O2-stimulated apoptosis than those in stiffer tubes. This protection was lost by pretreatment with an Akt inhibitor and restored in cells transfected with myristoylated Akt yet perfused in stiff tubes. Shear and stretch Akt signaling coupled to different upstream pathways as inhibition of vascular endothelial growth factor receptor 2 (VEGF2R) or disruption of caveolae blocked steady and pulse flow-mediated activation, yet did not suppress phosphorylated Akt induced by pulse perfusion in compliant tubes (concomitant stretch). Unlike Akt, reactive oxygen species, activated nuclear factor κB, and suppression of H2O2- stimulated c-Jun-N-terminal kinase activity were similar in pulse-perfused compliant and stiff tubes. Thus, cyclic endothelial cell stretch by pulse perfusion enhances Akt-dependent antiapoptosis above that induced by steady or phasic shear stress and, unlike the latter, signals via a VEGF2R/caveolae- independent pathway. Enhancing this stretch pathway may prove useful for improving endothelial function in stiff arteries.

Original languageEnglish
Pages (from-to)587-595
Number of pages9
JournalCirculation Research
Volume97
Issue number6
DOIs
Publication statusPublished - Sep 16 2005
Externally publishedYes

Fingerprint

Compliance
Pulse
Perfusion
Apoptosis
Caveolae
Endothelial Cells
Glycogen Synthase Kinase 3
Vascular Endothelial Growth Factor Receptor-2
1-Phosphatidylinositol 4-Kinase
Cytoprotection
JNK Mitogen-Activated Protein Kinases
Oxidants
Reactive Oxygen Species
Arterial Pressure
Cardiovascular Diseases
Arteries
Blood Pressure

Keywords

  • Apoptosis
  • Artery pulse
  • Endothelium
  • Stiffness
  • Vascular biology

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Reduced wall compliance suppresses Akt-dependent apoptosis protection stimulated by pulse perfusion. / Li, Manxiang; Chiou, Kuan Rau; Bugayenko, Artem; Irani, Kaikobad; Kass, David A.

In: Circulation Research, Vol. 97, No. 6, 16.09.2005, p. 587-595.

Research output: Contribution to journalArticle

Li, Manxiang ; Chiou, Kuan Rau ; Bugayenko, Artem ; Irani, Kaikobad ; Kass, David A. / Reduced wall compliance suppresses Akt-dependent apoptosis protection stimulated by pulse perfusion. In: Circulation Research. 2005 ; Vol. 97, No. 6. pp. 587-595.
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