Endocrine Abstracts

Stimulation of the corticotropin-releasing factor type 2 receptor (CRFR2) by its putative ligands the urocortins may influence cardiovascular function by regulating vascular tone and angiogenesis.

We examined whether chronic exposure to the CRFR2-selective ligand Urocortin 3 altered the ability of the receptor to modulate vascular functions by assessing arterial contractility and angiogenesis in response to Urocortin 3 both in control mice and in transgenic mice ubiquitously overexpressing Urocortin 3.

Urocortin 3 induced concentration-dependent relaxation in isolated mouse aortic rings which was altered, but not abolished, by removal of the endothelium. Dilator (Urocortin 3, acetylcholine) and constrictor (5-hydroxytryptamine) responses were unaltered in aortae from Urocortin 3 transgenic mice. Furthermore, conscious systolic blood pressure in Urocortin 3 transgenic mice did not differ from wildtype littermate controls (119±3 vs. 115±3 mgHg). Urocortin 3 (50 nM-5 μM) significantly inhibited angiogenesis in a concentration-dependent fashion in aortic ring cultures. The angiogenic response of aortic rings from Urocortin 3 transgenic mice (whether unstimulated or following exposure to VEGF or cortisol) was similar to those from wild-type littermates. Urocortin 3 significantly inhibited angiogenesis in sponges implanted subcutaneously under general anaesthesia in vivo (by 58±1%) and vessel growth was similarly inhibited in untreated sponges (by 52±3%) implanted into Urocortin 3 transgenic mice when compared to those implanted into controls.

These data suggest that Urocortin 3 is a vasodilator (acting via both endothelium-dependent and –independent mechanisms) and an anti-angiogenic factor in the mouse. The failure of chronic Urocortin 3 over-expression to alter these responses indicates CRFR2 is not down-regulated or desensitised in the vasculature of Urocortin 3 transgenic mice. In contrast, reduced angiogenesis in these mice confirms that endogenous Urocortin 3 may be an important inhibitor of new blood vessel growth.