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

Authors:
Michele Ciccarelli
Michele Ciccarelli
University of Salerno
Fisciano | Italy
Daniela Sorriento
Daniela Sorriento
Department of Clinical Medicine
Italy
Ersilia Cipolletta
Ersilia Cipolletta
Department of Clinical Medicine
Italy
Gaetano Santulli
Gaetano Santulli
Federico II University of Naples
Italy
Anna Fusco
Anna Fusco
Federico II University
Rui-Hai Zhou
Rui-Hai Zhou
United States
Andrea D Eckhart
Andrea D Eckhart
Duke University Medical Center
Durham | United States
Karsten Peppel
Karsten Peppel
Center for Translational Medicine
Arlington | United States

Br J Pharmacol 2011 Feb;162(3):712-21

Dipartimento di Medicina Clinica, Scienze Cardiovascolari ed Immunologiche, Università Federico II, Napoli, Italy.

Background And Purpose: There is much evidence supporting the role of β₂-adrenoceptors (β₂AR) in angiogenesis but the mechanisms underlying their effects have not been elucidated. Hence, we studied post-ischaemic angiogenesis in the hindlimb (HL) of β₂AR knock-out mice (β₂AR-/-) in vivo and explored possible molecular mechanisms in vitro.

Experimental Approach: Femoral artery resection (FAR) was performed in wild-type and β₂AR-/- 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 β₂AR (ADβ₂AR) was used to reinstate β₂ARs in β₂AR-/- 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 β₂AR-/- mice subjected to FAR, but was restored by gene therapy with ADβ₂AR. The proangiogenic responses to a variety of stimuli were impaired in β₂AR-/- EC in vitro. Moreover, removal of β₂ARs impaired the activation of NFκB, a transcription factor that promotes angiogenesis; neither isoprenaline (stimulates βARs) nor TNFα induced NFκB activation in β₂AR(-/-) EC. Interestingly, cAMP response element binding protein (CREB), a transcription factor that counter regulates NFκB, was constitutively increased in β₂AR(-/-) ECs. ADβ₂AR administration restored β₂AR membrane density, reduced CREB activity and reinstated the NFκB response to isoprenaline and TNFα.

Conclusions And Implications: Our results suggest that β₂ARs control angiogenesis through the tight regulation of nuclear transcriptional activity.

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Source
http://dx.doi.org/10.1111/j.1476-5381.2010.01078.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3041259PMC
February 2011
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19 Citations
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References

(Supplied by CrossRef)
Guide to Receptors and Channels (GRAC), 4th Edition
Alexander et al.
Br J Pharmacol 2009
Beta-adrenergic agonists exert their ‘anti-inflammatory’ effects in monocytic cells through the IkappaB/NF-kappaB pathway
Farmer et al.
Am J Physiol Lung Cell Mol Physiol 2000

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