Pannexins in the vasculature

Abstract

Pannexins (PANX1, PANX2, PANX3) are a family of large-pore, ion and metabolite channels present throughout the blood and lymphatic vascular networks. PANX1 has near-ubiquitous expression in the cardiovascular system and is the most highly studied pannexin in both homeostatic and disease conditions. In smooth muscle, endothelium, and blood cells, PANX1 acts at the cell surface as an ATP efflux channel to drive many vascular processes such as vasoconstriction, blood pressure, endothelial barrier function, platelet aggregation, and acute hypoxic responses. Conversely, PANX2 and PANX3 are understudied and exhibit a more intracellular localization pattern, with endothelial PANX3 modulating blood pressure through channel-independent mechanisms. In this review, we discuss the cellular localization and function of pannexins throughout the cardiovascular system, including resistance arteries, veins, lymphatics, large vessels, erythrocytes, platelets, pericytes, hearts, and lungs, as well as how this cellular activity corresponds to vascular physiology at the organism level. We also discuss the contribution of pannexins to the development and progression of various cardiovascular diseases, such as hypertension, edema, sepsis, atherosclerosis, aortic aneurysms, myocardial infarction, ischemia reperfusion, and thrombosis. In most cardiovascular diseases, PANX1 exacerbates disease development and progression, as evidenced by PANX1 channel blockade or genetic deletion in murine models improving disease outcomes, whereas the beneficial action of PANX3 in healthy vessels seems to be lost in conditions such as hypertension. With the prevalence of cardiovascular diseases and the associated burden on patients and healthcare systems, pannexin-based therapeutics may represent a novel alternative or combinatorial strategy for the treatment of many vascular conditions.

Keywords: arteries; endothelial cells; inflammation; ischemia reperfusion; smooth muscle cells.

Figure 1.

Topology and post-translational modifications of mouse PANX1, PANX2 and PANX3. NT, N-terminus; EL1, extracellular loop 1; EL2, extracellular loop 2; CT, C-terminus.

Figure 2.

Pannexin (Panx) mRNA expression across the endothelium. Publicly available single cell RNA-sequencing data from endothelial cells isolated from male mice fed a normal chow diet was used to investigate pannexin expression across the endothelium. Data from both the mesentery and adipose endothelial cells were combined, and endothelial identity was determined based on known markers as previously described (45). GEO Accession Number: GSE235192. % Exp., percent expressed; Avg. Exp., average expression.

Figure 3.

PANX1 regulation of α-adrenergic vasoconstriction. Upon stimulation of α1D-adrenergic receptor (α-1DAR) with its agonist norepinephrine (NE) on the cell surface of smooth muscle cells, the receptor aggregates with PANX1 channels in close proximity to caveolae comprised primarily of caveolin 1 (CAV1) (1). α-1DAR signaling through Src family kinases (SFK) drives phosphorylation of PANX1 on the Y198 intracellular loop residue (2). Phosphorylation activates PANX1 channel ATP release, leading to downstream purinergic (P2) receptor signaling (3) and blood vessel constriction (4).

Figure 4.

PANX3 and BCLiP interactions. Side view of dimeric PANX3, with the monomers in shades of gray and rendered as a transparent surface, and the protein backbone rendered as cartoon. The putative binding cleft for the BCLiP mimetic peptide in PANX3 is depicted in beige. Two putative binding orientations of BCLiP are colored blue and orange and rendered as a cartoon.

Figure 5.

Pannexin (PANX) expression and function in the arterial and venous vascular network and associated diseases. EC, endothelial cell; SMC, smooth muscle cell; RBC, red blood cell; BCL6, B cell lymphoma 6.

Figure 6.

Pannexin (PANX) expression and function in the lymphatic vasculature and associated diseases. HDLECs, human dermal lymphatic endothelial cells; VEGF-C, vascular endothelial growth factor C.