Vascular β-adrenoceptor function in hypertension and in ageing

Abstract

Functional β-adrenoceptors (β-AR) have been identified and characterized in blood vessels under in vivo conditions as well as in vascular smooth muscle cells (SMC) grown in culture. Agonist occupancy of β-AR activates adenylyl cyclase (AC) via the stimulatory guanine nucleotide-binding protein (Gs) and leads to elevations in intracellular adenosine 3',5'-cyclic monophosphate levels (cAMP). Increased cAMP activates the cAMP-dependent protein kinase (PKA), with subsequent phosphorylation of various target proteins. This β-AR pathway interacts with several other intracellular signalling pathways via cross-talk, so that activation by β-AR agonists may also modulate other second messengers and protein kinases. SMC β-AR play an important role in SMC function. In intact blood vessels they mediate SMC relaxation by various intracellular mechanisms, ultimately causing a decrease in intracellular Ca2+levels. In cultured SMC, activation of the β-AR pathway results in inhibition of cellular proliferation, the development of SMC polyploidy, and SMC apoptosis. Blood vessels from hypertensive animals are characterized by an increase in SMC cell mass, a greater incidence of SMC polyploidy in the aorta, and an impairment in the β-agonist-mediated SMC relaxation. Some of these changes may result from an attenuation of β-AR function due to agonist-induced receptor desensitization caused by the uncoupling of receptors from the Gs-AC system. The phosphorylated β-AR may in turn trigger new signals and activate different intracellular pathways. However, the details of these mechanisms are still unresolved. Since functional β-AR play such a prominent and multi-faceted role in SMC function, it is important to understand how these diverse physiological effects are mediated by this receptor system, and how they contribute to the development of hypertension. With ageing, a decrease in β-AR-Gs-AC coupling is observed, and this is implicated in the reduced responsiveness of SMC. The similarities in SMC β-AR functional changes in hypertension and in ageing suggest that the underlying mechanisms are also analogous.Key words: smooth muscle, β-adrenoceptors, cyclic AMP, protein kinase A, cell proliferation, polyploidy, relaxation, apoptosis, hypertension, ageing.