Ischemic neoangiogenesis enhanced by β2-adrenergic receptor overexpression -: A novel role for the endothelial adrenergic system

被引:150
作者
Iaccarino, G
Ciccarelli, M
Sorriento, D
Galasso, G
Campanile, A
Santulli, G
Cipolletta, E
Cerullo, V
Cimini, V
Altobelli, GG
Piscione, F
Priante, O
Pastore, L
Chiariello, M
Salvatore, F
Koch, WJ
Trimarco, B
机构
[1] Univ Naples Federico II, Dipartimento Med Clin & Sci Cardiovasc & Immunol, I-80131 Naples, Italy
[2] Univ Naples Federico II, Dipartimento Biochim & Biotecnol Med, I-80131 Naples, Italy
[3] CEINGE Biotecnol Avanzate, Naples, Italy
[4] Univ Naples Federico II, Dipartimento Sci Biomorfol & Funzionali, I-80131 Naples, Italy
[5] Thomas Jefferson Univ, Ctr Translat Med, Philadelphia, PA 19107 USA
[6] IRCCS Neuromed, Pozzilli, Italy
关键词
angiogenesis; rats; polymorphism; hypertension; in vivo digital angiography;
D O I
10.1161/01.RES.0000191541.06788.bb
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
beta(2)-Adrenergic receptors (beta(2)ARs) are widely expressed, although their physiological relevance in many tissues is not yet fully understood. In vascular endothelial cells, they regulate NO release and vessel tone. Here we provide novel evidence that beta(2)ARs can regulate neoangiogenesis in response to chronic ischemia. We used in vivo adenoviral-mediated gene transfer of the human beta(2)AR to the endothelium of the rat femoral artery and increased beta(2)AR signaling resulting in ameliorated angiographic blood flow and hindlimb perfusion after chronic ischemia. Histological analysis confirmed that beta(2)AR overexpression also produced benefits on capillary density. The same maneuver partially rescued impaired angiogenesis in spontaneously hypertensive rats (SHR), whereas gene delivery of the G-protein coupling defective mutant Ile164 beta(2)AR failed to provide ameliorations. Stimulation of endogenous and overexpressed beta(2)AR on endothelial cells in vitro was found to regulate cell number by inducing proliferation and [H-3]-thymidine incorporation through means of extracellular receptor-activated kinase and vascular endothelial growth factor. The beta(2)AR also has novel effects on endothelial cell number through stimulation of proapoptosis and antiapoptosis pathways involving p38 mitogen-activated protein kinase and PI3-kinase/Akt activation. Therefore, beta(2)ARs play a critical role in endothelial cell proliferation and function including revascularization, suggesting a novel and physiologically relevant role in neoangiogenesis in response to ischemia.
引用
收藏
页码:1182 / 1189
页数:8
相关论文
共 40 条
[1]   TROPHIC EFFECTS OF PERIPHERAL ADRENERGIC-NERVES ON VASCULAR STRUCTURE [J].
BEVAN, RD .
HYPERTENSION, 1984, 6 (06) :19-26
[2]   Emerging role of homo- and heterodimerization in G-protein-coupled receptor biosynthesis and maturation [J].
Bulenger, S ;
Marullo, S ;
Bouvier, M .
TRENDS IN PHARMACOLOGICAL SCIENCES, 2005, 26 (03) :131-137
[3]   Molecular mechanisms of blood vessel formation [J].
Bussolino, F ;
Mantovani, A ;
Persico, G .
TRENDS IN BIOCHEMICAL SCIENCES, 1997, 22 (07) :251-256
[4]   The β2-adrenergic receptor delivers an antiapoptotic signal to cardiac myocytes through Gi-dependent coupling to phosphatidylinositol 3′-kinase [J].
Chesley, A ;
Lundberg, MS ;
Asai, T ;
Xiao, RP ;
Ohtani, S ;
Lakatta, EG ;
Crow, MT .
CIRCULATION RESEARCH, 2000, 87 (12) :1172-1179
[5]   Inhibition of Src-like kinases reveals Akt-dependent and -independent pathways in insulin-like growth factor I-mediated oligodendrocyte progenitor survival [J].
Cui, QL ;
Zheng, WH ;
Quirion, R ;
Almazan, G .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (10) :8918-8928
[6]   Cyclins and cdks in development and cancer: a perspective [J].
Deshpande, A ;
Sicinski, P ;
Hinds, PW .
ONCOGENE, 2005, 24 (17) :2909-2915
[7]   Rescue of impaired angiogenesis in spontaneously hypertensive rats by intramuscular human tissue kallikrein gene transfer [J].
Emanueli, C ;
Salis, MB ;
Stacca, T ;
Gaspa, L ;
Chao, J ;
Chao, L ;
Piana, A ;
Madeddu, P .
HYPERTENSION, 2001, 38 (01) :136-141
[8]   Norepinephrine induces vascular endothelial growth factor gene expression in brown adipocytes through a β-adrenoreceptor/cAMP/protein kinase A pathway involving Src but independently of Erk1/2 [J].
Fredriksson, JM ;
Lindquist, JM ;
Bronnikov, GE ;
Nedergaard, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (18) :13802-13811
[9]   The Ile164 β2-adrenoceptor polymorphism alters salmeterol exosite binding and conventional agonist coupling to Gs [J].
Green, SA ;
Rathz, DA ;
Schuster, AJ ;
Liggett, SB .
EUROPEAN JOURNAL OF PHARMACOLOGY, 2001, 421 (03) :141-147
[10]  
GREEN SA, 1993, J BIOL CHEM, V268, P23116