Purinergic signaling is central in the regulation of vascular tone, which can be mediated by adenosine 5′ triphosphate (ATP) and its metabolic breakdown products. Interestingly, ATP can act as either a vasoconstrictor or vasodilator. In the vascular wall, there are multiple sources for ATP; for example, ATP can be released from perivascular nerves and endothelial cells, as well as from circulating erythrocytes. Previously, we showed that cultured smooth muscle cells (SMC) release ATP in response to phenylephrine, an α1-adrenoreceptor (α1AR) agonist, and that ATP, purinergic receptors, and the ATP-release channel formed by pannexin1 (Panx1) are synergistically involved in phenylephrine-mediated vasoconstriction.
The pannexins comprise a family of membrane channels similar to innexins, the gap junction-forming proteins in invertebrates. Pannexins share topological similarities but no sequence homology with the gap junction-forming connexin proteins in vertebrates, thus pannexins represent a distinct class of channel-forming proteins. Besides Panx1, two other isoforms have been described, Panx2 and Panx3. Panx1 is the most widely distributed in vertebrates, whereas the presence of Panx2 and Panx3 is restricted to specific tissues. In the systemic vasculature, Panx1 is found in all endothelial cells, but only some SMC; the protein is absent in SMC of conduit arteries and becomes more abundant as the resistance of the arteries increases. Functionally, in apoptotic cells Panx1 channels are activated for cell clearance to support the innate immune response, and in neurons, Panx1 channels are activated in response to cerebral ischemia or to decreases in circulating oxygen. Because Panx1 forms large-pore channels allowing the release of ATP and other intracellular ions and metabolites, channel activity is regulated by various receptors to avoid loss of cellular electrochemical and metabolic homeostasis, which would result in rapid cell death. For example, Panx1-dependent ATP release occurs in response to activation of thrombin receptors, N-methyl-D-aspartate (NMDA) receptors, histamine receptors, and purinergic receptors.
There is a long felt need in the art for compositions and methods useful for regulating blood pressure and for maintaining blood pressure homeostasis. The present invention satisfies these needs.