Impact of Estrogen on Purinergic Signaling in Microvascular Disease

Figure 1. Adenosine production and metabolism. Extracellular adenosine is rapidly deaminated to inosine or shuttled intracellularly via ENT transmembrane channels. Intracellular adenosine is either deaminated to inosine via adenosine deaminase (ADA), recycled in the purine salvage pathway, or re-phosphorylated to ATP. 5′NT: 5′-nucleotidase, AC: adenylate cyclase, ADA: adenosine deaminase, ADP: adenosine diphosphate, ADK: adenosine kinase, AK: adenylate kinase, AMP: adenosine monophosphate, ATP: adenosine 5′-triphosphate, cAMP: cyclic adenosine monophosphate, ENT: equilibrative nucleoside transporter, NDPK: nucleoside-diphosphate kinase: PDE; phosphdiesterase; SAHH: S-adenosyl homocysteine hydrolase.

Figure 2. Adenosine activity in endothelial cells. Extracellular adenosine interacts with endothelial cells in several ways resulting in vasoprotection. 1. Adenosine activates ADORA receptors on the cell surface stimulating activation of pathways including PI3K and PKA signaling. 2. Adenosine is transported intracellularly through ENT channels where it can be deaminated to inosine or utilized in further downstream signaling. ADA: adenosine deaminase, ADK: adenosine kinase, AKT: protein kinase B, AMP: adenosine monophosphate, ATP: adenosine 5′-triphosphate, cAMP: cyclic adenosine monophosphate, eNOS: endothelial nitric oxide synthase, ENT: equilibrative nucleoside transporter, NO: nitric oxide, PKA: protein kinase A, PI3K: phosphatidylinositol-3 kinase.

Figure 3. ATP production and transport. ATP is produced 1. through the metabolism of glucose (glycolysis), 2. through the metabolism of pyruvate in the tricarboxylic acid (TCA) cycle, and 3. through oxidative phosphorylation in the electron transport chain. Once intracellular, ATP is released via transmembrane transporter channels, pannexins and connexins. Intracellular ATP is also released though controlled exocytosis. AC: adenylate cyclase, ADP: adenosine diphosphate, AMP: adenosine monophosphate, ATP: adenosine 5′-triphosphate, cAMP: cyclic adenosine monophosphate, Cyt C: cytochrome C.

Figure 4. ATP pathway activation in endothelial cells. Extracellular ATP is present due to uncontrolled release following inflammatory and/or ischemic events. ATP stimulates endothelial cells through activation of several cell surface receptors. 1. ATP activates P2Y receptors on the cell surface stimulating downstream activation of PKC signaling, including inhibition of NO (noted by blunt arrowhead). 2. ATP activates P2X receptors on cell surface leading to calcium release and increased NLRP3 inflammasome and ROS activity. ADP: adenosine diphosphate, ATP: adenosine 5′-triphosphate, IL-1β: interleukin-1β, NF-κB: nuclear factor-kappa B, NLRP3: nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3, NO: nitric oxide, PKC: protein kinase C, P2X: purinergic P2X receptor, P2Y: purinergic P2Y receptor, ROS: reactive oxygen species.

Figure 5. Effects of estrogen on vascular function: The role of estrogen on endothelial processes with a focus on purinergic-specific pathways. ↑ denotes a positive effect, ⊥ denotes an inhibitory effect. ADP: adenosine diphosphate, ATP: adenosine 5′-triphosphate, CD39: ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD1), CD73: ecto-5′-nucleotidase (NT5E).