Table 2.
Local mediators of vascular tone and vessel patency
| Pathway | Early Pathway Events | Downstream Signaling | Effects | Main Physiological Function | Reference Nos. | Evidence for Pathway Modulated by Hmox1 |
|---|---|---|---|---|---|---|
| Myogenic constriction | Activation of an unknown mechanosensor | Increase in phospholipase C, inositol 1,4,5-trisphosphate, protein kinase C, VSMC depolarization, VSMC [Ca2+]i, myosin light-chain Ca2+ sensitivity and actin polymerization | Constriction | Autoregulation of blood flow, capillary pressure stabilization | 178, 253, 366, 588 | 379 |
| Cytochrome P-450 metabolism of arachidonic acid | Formation of 20-hydroxyeicosatetraenoic acid, increase in protein kinase C, decrease in VSMC potassium channel opening, increase in VSMC [Ca2+]i | Constriction | Autoregulation of blood flow, capillary pressure stabilization | 270, 330 | 102 | |
| Cyclooxygenase metabolism of arachidonic acid | Production of prostacyclin and stimulation of IP receptor | Increase in adenylate cyclase, cAMP, protein kinase A activity, VSMC hyperpolarization and decrease in VSMC [Ca2+]i | Relaxation | Flow mediated dilation, endothelium-dependent, observed when other mediators are inhibited, renal blood flow regulation, platelet inhibition | 93, 94, 197, 256 | 299 |
| Production of PGE2 and stimulation of EP1, EP2, EP3 and EP4 receptors | EP2, EP4: Increase in adenylate cyclase, protein kinase A, K+ efflux, decrease in VSMC [Ca2+]i | EP2, EP4: relaxation | Renin secretion and systemic vascular tone | 4, 88, 431, 469, 527 | 47, 165 | |
| EP1, EP3: Increase in phospholipase C, inositol 1,4,5-trisphosphate and decrease in cAMP | EP1, EP3: constriction | |||||
| Production of thromboxane A2 and stimulation of TP receptors | Increase in phospholipase C, inositol 1,4,5-trisphosphate, VSMC [Ca2+]i, and myosin light-chain Ca2+ sensitivity, decrease in adenylate cyclase and cAMP, increase in phosphodiesterase expression, inhibition of endothelial hyperpolarization, increase in superoxide production | Constriction | Regulation of vascular tone, inhibition of EC-derived hyperpolarization, increase in reactive species, cross-reactivity with other prostanoid receptors under disease conditions | 191, 287, 355, 364, 378 | 471 | |
| Nitric oxide | sGC | Increase in cGMP, protein kinase G, receptor modulation, VSMC hyperpolarization; decrease in [Ca2+]i and myosin light-chain Ca2+ sensitivity | Relaxation | Blood pressure regulation, relaxation, inhibition of platelet aggregation, regulation of cardiac contractility | 44, 87, 443, 463, 526 | 216 |
| Carbon monoxide | sGC/BKca | Increase in; cGMP, protein kinase G and activation of BKca channels | Relaxation | Blood pressure regulation, relaxation | 147, 216, 379, 574, 587, 603 | |
| High CO concentration in skeletal muscle | Negative modulation of the NO pathway | Constriction | 203, 212 | |||
| EC-derived hyperpolarization of VSMC (not mediated by NO or cyclooxygenase-derived products) | K+ efflux through endothelial calcium-activated K+ channels | Activation of VSMC Kir and Na+-K+-ATPase channels, VSMC hyperpolarization leading to decreased VSMC [Ca2+]i | Relaxation | Regulation of vascular tone in resistance arteries, regulation of blood pressure, conduction of relaxation along arterial branches | 49, 97, 125, 253, 254, 479 | 298 |
| Electrical conductance through junctional proteins | Connexins mediate electrical conduction of hyperpolarization along EC and VSMC leading to decreased VSMC [Ca2+]i | Relaxation | Regulation of vascular tone of potential importance during functional antagonism of relaxation, conducted relaxation | 127, 345, 608 | ||
| Small molecule movement through myoendothelial gap junctions | Inositol 1,4,5-trisphosphate or Ca2+ movement through myoendothelial gap junctions, increase in EC [Ca2+]i, activation of eNOS and/or IKCa channels, subsequent activation of pathways described above | Relaxation | Regulation of vascular tone, VSMC negative feedback to counteract constriction | 274, 387, 460, 545 | ||
| Cytochrome P-450 metabolism of arachidonic acid | Epoxyeicosatrienoic acid act in: 1) autocrine manner raising EC [Ca2+]i through TRP receptors and subsequently activating Ca2+-activated K+ channels; and/or 2) paracrine action whereby epoxyeicosatrienoic acids diffuse to VSMC activating unidentified receptors, VSMC Ca2+- activated K+ channels and subsequent hyperpolarization and closure of voltage-gated Ca2+ channels | Relaxation | Regulation of vascular tone in response to cyclic stretch and shear flow and produced in inflammatory states | 58, 137, 190, 562 | 453, 454 | |
| Lipoxygenase metabolism of arachidonic acid | Formation of trihydroxyeicosatrienoic acids, hydroxyepoxyeicosatrienoic acids, and hydroxyeicosatetraenoic acids; VSMC hyperpolarization through K+ efflux | Relaxation | Regulation of vascular tone through hyperpolarization, roles in inflammation | 151–153, 638 | ||
| EC source of hydrogen peroxide | Oxidation of protein kinase G1α, activation of BKCa channels, VSMC hyperpolarization, decrease in VSMC [Ca2+]i | Relaxation | Proposed EC-derived hyperpolarizing factor. Mice with protein kinase G1α increased blood pressure despite normal response to NO | 53, 376, 429 | ||
| EC source of hydrogen sulfide | Formation of sulfide, nitrogen hybrid groups, enhanced NO donor activity, oxidation of protein kinase G1α, VSMC hyperpolarization, and decrease in [Ca2+]i | Relaxation | Proposed EC-derived hyperpolarizing factor | 95, 96, 300, 512 | ||
| EC source of bradykinin | Activation of B1 and B2 receptors, increase in EC [Ca2+]i, EC hyperpolarization, formation of epoxyeicosatrienoic acids, activation of BKCa channels | Relaxation | Inflammatory responses, relaxation and pain | 125, 589 | ||
| Endothelin-1 | ETA receptor | Increase in phospholipase C, inositol 1,4,5-trisphosphate, diacylglycerol, protein kinase C, and VSMC [Ca2+]i, increased superoxide production | Constriction | Regulation of vascular tone, more pronounced effects in age and disease | 105, 251, 284, 602 | |
| ETB Receptor | Increase in EC [Ca2+]i, increased prostacyclin and NO production | Relaxation | 105, 126, 632 | |||
| Angiotensin | Angiotensin type 1 receptor | Increase in phospholipases C, A2 and D; inositol 1,4,5-trisphosphate; diacylglycerol; VSMC [Ca2+]I; RhoA kinase activation. Stimulation of protein kinase C, BKca channel internalization, NADPH oxidase activation, increased superoxide production | Constriction | Regulation of vascular tone, electrolyte and blood volume and systemic blood pressure | 280, 356 | |
| Angiotensin type 2 receptor | Angiotensin II metabolism to angiotensin (1–7), III, and IV; increased NO release | Relaxation | 154, 155 | 189 |