Endothelial α₁‐adrenoceptors regulate neo‐angiogenesis

Abstract

Background and purpose: Intact endothelium plays a pivotal role in post-ischaemic angiogenesis. It is a phenomenon finely tuned by activation and inhibition of several endothelial receptors. The presence of a 1 -adrenoceptors on the endothelium suggests that these receptors may participate in regenerative phenomena by regulating the responses of endothelial cells involved in neo-angiogenesis. Experimental approach: We evaluated the expression of the subtypes of the a 1 -adrenoceptor in isolated endothelial cells harvested from Wistar-Kyoto (WKY) rats. We explored the possibility these a 1 -adrenoceptors may influence the pro-angiogenic phenotype of endothelial cells in vitro. In vivo, we used a model of hindlimb ischaemia in WKY rats, to assess the effects of a 1 adrenoceptor agonist or antagonist on angiogenesis in the ischaemic hindlimb by laser Doppler blood flow measurements, digital angiographies, hindlimb perfusion with dyed beads and histological evaluation. Key results: In vitro, pharmacological antagonism of a 1 -adrenoceptors in endothelial cells from WKY rats by doxazosin enhanced, while stimulation of these adrenoceptors with phenylephrine, inhibited endothelial cell proliferation and DNA synthesis, ERK and retinoblastoma protein (Rb) phosphorylation, cell migration and tubule formation. In vivo, we found increased a 1 -adrenoceptor density in the ischaemic hindlimb, compared to non-ischaemic hindlimb, suggesting an enhanced a 1 -adrenoceptor tone in the ischaemic tissue. Treatment with doxazosin (0.06 mg kg À1 day À1 for 14 days) did not alter systemic blood pressure but enhanced neo-angiogenesis in the ischaemic hindlimb, as measured by all our assays. Conclusions: Our findings support the hypothesis that the a 1 -adrenoceptors in endothelial cells provide a negative regulation of angiogenesis.

Isoindolone derivative QSN-10c induces leukemic cell apoptosis and suppresses angiogenesis via PI3K/AKT signaling pathway inhibition

“…Therefore, anti-angiogenic and angio-prevention therapies represent promising approaches to control tumor growth and metastasis [6,7] . Neoangiogenesis is a highly ordered, multistep molecular process tightly regulated in endothelial cells [8,9] that involves the proliferation of endothelial cells (ECs), motility, cell realignment, vessel formation, and the production of a new basement membrane [1,10,11] . Of the numerous growth factors and cytokines that have been shown to possess angiogenic effects, vascular endothelial growth factor (VEGF) is an attractive therapeutic target for the development of novel anticancer agents [12] .…”

Intracardiac Injection of AdGRK5-NT Reduces Left Ventricular Hypertrophy by Inhibiting NF-κB–Dependent Hypertrophic Gene Expression

“…Blood pressure (BP) was measured as described previously, 17,18 and the record of both systolic (SBP) and diastolic (DBP) BPs was taken using a pressure transducer catheter (Mikro-Tip, Millar Instruments, Inc). The catheters already placed in the ascending aorta were then advanced further into LV to record the maximal and minimal first derivatives of pressure over time (dP/dt maximum and dP/dt minimum), as indices of global cardiac contractility and relaxation.…”

Endothelial Cells Are Able to Synthesize and Release Catecholamines Both In Vitro and In Vivo

“…[7][8][9][10][11][12][13][14] To this purpose, the endothelium is regulated in a fine way by a series of receptors that are expressed on its surface, including adrenergic receptors (ARs), such as ␣ 1 and ␤ 2 AR. 15,16 Circulating catecholamines are thought to be the natural agonist of these receptors, giving the fact that ECs are not reached by sympathetic innervation. 1 The endothelium derives from the embrional mesenchimal sheet, so it does the population of myeloid lineage-restricted bone marrow progenitors.…”