Impaired neoangiogenesis in β2-adrenoceptor gene-deficient mice: Restoration by intravascular human β2-adrenoceptor gene transfer and role of NFkB and CREB transcription factors

Michele Ciccarelli, Daniela Sorriento, Ersilia Cipolletta, Gaetano Santulli, Anna Fusco, Rui Hai Zhou, Andrea D. Eckhart, Karsten Peppel, Walter J. Koch, Bruno Trimarco, Guido Iaccarino

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Background and Purpose: There is much evidence supporting the role of β 2-adrenoceptors (β 2AR) in angiogenesis but the mechanisms underlying their effects have not been elucidated. Hence, we studied post-ischaemic angiogenesis in the hindlimb (HL) of β 2AR knock-out mice (β 2AR-/-) in vivo and explored possible molecular mechanisms in vitro. Experimental Approach: Femoral artery resection (FAR) was performed in wild-type and β 2AR-/-mice and adaptive responses to chronic HL ischaemia were explored; blood flow was measured by ultrasound and perfusion of dyed beads, bone rarefaction, muscle fibrosis and skin thickness were evaluated by immunoflourescence and morphometric analysis. Intrafemoral delivery of an adenovirus encoding the human β 2AR (ADβ 2AR) was used to reinstate β 2ARs in β 2AR-/-mice. Molecular mechanisms were investigated in mouse-derived aortic endothelial cells (EC) in vitro, focusing on NFκB activation and transcriptional activity. RESULTS Angiogenesis was severely impaired in β 2AR-/-mice subjected to FAR, but was restored by gene therapy with ADβ 2AR. The proangiogenic responses to a variety of stimuli were impaired in β 2AR-/-EC in vitro. Moreover, removal of β 2ARs impaired the activation of NFκB, a transcription factor that promotes angiogenesis; neither isoprenaline (stimulates βARs) nor TNFα induced NFκB activation in β 2AR -/-EC. Interestingly, cAMP response element binding protein (CREB), a transcription factor that counter regulates NFκB, was constitutively increased in β 2AR -/-ECs. ADβ 2AR administration restored β 2AR membrane density, reduced CREB activity and reinstated the NFκB response to isoprenaline and TNFα. Conclusions and Implications: Our results suggest that β 2ARs control angiogenesis through the tight regulation of nuclear transcriptional activity.

Original languageEnglish (US)
Pages (from-to)712-721
Number of pages10
JournalBritish Journal of Pharmacology
Volume162
Issue number3
DOIs
StatePublished - Feb 1 2011
Externally publishedYes

Keywords

  • NFkB activity
  • adrenergic signaling
  • gene therapy
  • ischaemic hindlimb

ASJC Scopus subject areas

  • Pharmacology

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    Ciccarelli, M., Sorriento, D., Cipolletta, E., Santulli, G., Fusco, A., Zhou, R. H., Eckhart, A. D., Peppel, K., Koch, W. J., Trimarco, B., & Iaccarino, G. (2011). Impaired neoangiogenesis in β2-adrenoceptor gene-deficient mice: Restoration by intravascular human β2-adrenoceptor gene transfer and role of NFkB and CREB transcription factors. British Journal of Pharmacology, 162(3), 712-721. https://doi.org/10.1111/j.1476-5381.2010.01078.x