William B. Campbell, PhD
- Pharmacology and Toxicology
BS, Pharmacy, University of Texas, 1970
Endothelial cells are the vascular cells that line the lumen of blood vessels; they are in contact with smooth muscle cells on one side and circulating blood cells on the other. Endothelium modulates vascular tone and provides a nonthrombogenic surface for blood vessels. These actions are mediated through the release of soluble mediators and some of these mediators are metabolites of arachidonic acid. Arachidonic acid undergoes a variety of oxidation reactions to yield several families of biologically active lipids called eicosanoids. The principal enzymatic pathways of arachidonic acid metabolism include cyclooxygenase, lipoxygenases and cytochrome P450 epoxygenase. The products of these pathways include the prostaglandins, thromboxane, leukotrienes and others. Eicosanoids act as local hormones to regulate cell function and to communicate among cells. Endothelial cells, for example, synthesize prostacyclin from arachidonic acid. It causes relaxation of vascular smooth muscle and inhibits platelet aggregation. Research in our laboratory involves the isolation and identification of new metabolites of arachidonic acid and other endothelial mediators of vascular function. Once identified, the biological activities of the mediators are determined, their mechanism of action examined and the regulation of their synthesis investigated. These studies are important to our understanding of the causes of hypertension and ischemic heart disease and provide insights into new therapies.
We are studying the regulation of vascular tone and adrenal steroidogenesis by endothelial cell factors:
Smooth Muscle Cells
Like prostacyclin, epoxyeicosatrienoic acids (EETs) are also synthesized from arachidonic acid by the coronary vascular endothelium. While prostacyclin is made by cyclooxygenase, the EETs are synthesized by cytochrome P450 epoxygenase. The EETs also cause coronary vasodilation. The hormone acetylcholine stimulates the release of prostacyclin and EETs from endothelial cells, and these eicosanoids mediate a portion of the endothelium-dependent relaxations to this hormone. EETs cause vasodilation by opening calcium-activated potassium channels in smooth muscle cells and thereby decreasing the membrane potential of these cells. Thus, the EETs represent endothelium-derived hyperpolarizing factors (EDHFs). Using cultured cells, patch clamp and biochemical assays, we find that EETs activate these potassium channels by activating a guanine nucleotide binding protein. In isolated membranes, 14,15-EET radioligands exhibit specific, saturable, reversible binding that is inhibited by GTP suggesting a receptor-mediated pathway is involved. Future studies will (1) investigate the mechanism of action of the EETs by characterizing the cellular binding sites, receptors, (2) characterize specific EET agonist analogs and (3) identify specific inhibitors of EET synthesis or action.
We are also investigating the hypothesis that endothelial cells produce other metabolites of arachidonic acid that regulate vascular tone. Endothelial cells from aortic and mesenteric arteries release two lipoxygenase metabolites of arachidonic acid that causes vasodilation of smooth muscle by activations of small conductance, calcium-activated potassium channels and membrane hyperpolarization. Thus, they also function as EDHFs. We have identified these new vasodilators as 15-hydroxy-11,12-epoxyeicosatrienoic acid and 11,12,15-trihydroxyeicosatrienoic acid. These metabolites are produced by the sequential action of 15-lipoxygenase and a hydroperoxide isomerase on arachidonic acid. The expression of 15-lipoxygenase and the activity of this vasodilator pathway is enhanced by hypoxia, estrogen, hypercholesterolemia, interleukin-13 and other hormones. Thus, the 15-lipoxygenase pathway represents the inducible EDHF. Studies are in progress to further characterize the regulation of 15-lipoxygenase expression in cardiovascular disease models and determine the mechanism of action of these eicosanoids.
Adrenal Glomerulosa Cells
Adrenal glomerulosa cells synthesize and release aldosterone. This steroid is the major mineralocorticoid of the body. It regulates the excretion of sodium and potassium and is involved in the long-term control of blood pressure. The synthesis of aldosterone is regulated principally by angiotensin II, potassium and adrenocorticotropic hormone. However, evidence from our laboratory indicates that the synthesis of aldosterone is modulated by nitric oxide released by adrenal capillary endothelial cells. This is not surprising since the adrenal is a highly vascular gland and the aldosterone producing cells are in close proximity to the capillary endothelial cells. For the adrenal gland to function, adrenal blood flow must increase with steroid synthesis to deliver oxygen, cholesterol and cofactors and to carry the steroids to target tissues. We have shown that steroidogenic stimuli such as angiotensin II and adrenocorticotropic hormone release EETs from steroidogenic cells that dilate adrenal arterioles increasing adrenal blood flow. Future studies will define the mechanism of action of EETs on adrenal arteriolar smooth muscle cells, define the influence of adrenal steroids, identify other vasoactive factors made by steroidogenic cells and determine the pathways of EET synthesis and degradation by steroiodgenic cells.
Macrophage 12(S)-HETE Enhances Angiotensin II-Induced Contraction by a BLT2 (Leukotriene B4 Type-2 Receptor) and TP (Thromboxane Receptor)-Mediated Mechanism in Murine Arteries.
(Kriska T, Herrnreiter A, Pfister SL, Adebesin A, Falck JR, Campbell WB.) Hypertension. 2022 Jan;79(1):104-114 PMID: 34784723 PMCID: PMC8849474 SCOPUS ID: 2-s2.0-85120936681 11/18/2021
The Histamine 3 Receptor Is Expressed in the Heart and Its Activation Opposes Adverse Cardiac Remodeling in the Angiotensin II Mouse Model.
(McCaffrey SL, Lim G, Bullock M, Kasparian AO, Clifton-Bligh R, Campbell WB, Widiapradja A, Levick SP.) Int J Mol Sci. 2020 Dec 21;21(24) PMID: 33371319 PMCID: PMC7767352 SCOPUS ID: 2-s2.0-85098332503 12/30/2020
1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), a soluble epoxide hydrolase inhibitor, lowers L-NAME-induced hypertension through suppression of angiotensin-converting enzyme in rats.
(Bukhari IA, Alorainey BI, Al-Motrefi AA, Mahmoud A, Campbell WB, Hammock BD.) Eur Rev Med Pharmacol Sci. 2020 Aug;24(15):8143-8150 PMID: 32767352 PMCID: PMC7990106 SCOPUS ID: 2-s2.0-85089301773 08/09/2020
Ervin G. Erdös, MD, (October 16, 1922-November 17, 2019).
(Campbell WB, Skidgel RA, Alhenc-Gelas F.) Hypertension. 2020 Jun;75(6):1360-1362 PMID: 32306770 SCOPUS ID: 2-s2.0-85084694381 04/21/2020
Epoxyeicosatrienoic acid analog EET-B attenuates post-myocardial infarction remodeling in spontaneously hypertensive rats.
(Neckář J, Hye Khan MA, Gross GJ, Cyprová M, Hrdlička J, Kvasilová A, Falck JR, Campbell WB, Sedláková L, Škutová Š, Olejníčková V, Gregorovičová M, Sedmera D, Kolář F, Imig JD.) Clin Sci (Lond). 2019 Apr 30;133(8):939-951 PMID: 30979784 PMCID: PMC6492034 SCOPUS ID: 2-s2.0-85064975365 04/14/2019
GPR40 is a low-affinity epoxyeicosatrienoic acid receptor in vascular cells.
(Park SK, Herrnreiter A, Pfister SL, Gauthier KM, Falck BA, Falck JR, Campbell WB.) J Biol Chem. 2018 Jul 06;293(27):10675-10691 PMID: 29777058 PMCID: PMC6036206 SCOPUS ID: 2-s2.0-85049468178 05/20/2018
Deactivation of 12(S)-HETE through (ω-1)-hydroxylation and β-oxidation in alternatively activated macrophages.
(Kriska T, Thomas MJ, Falck JR, Campbell WB.) J Lipid Res. 2018 Apr;59(4):615-624 PMID: 29472381 PMCID: PMC5880500 SCOPUS ID: 2-s2.0-85045010822 02/24/2018
Effect of Angiotensin II and ACTH on Adrenal Blood Flow in the Male Rat Adrenal Gland In Vivo.
(Shah AJ, Kriska T, Gauthier KM, Falck JR, Campbell WB.) Endocrinology. 2018 Jan 01;159(1):217-226 PMID: 29140411 PMCID: PMC5761607 SCOPUS ID: 2-s2.0-85040721869 11/16/2017
Obligatory Metabolism of Angiotensin II to Angiotensin III for Zona Glomerulosa Cell-Mediated Relaxations of Bovine Adrenal Cortical Arteries.
(Kopf PG, Park SK, Herrnreiter A, Krause C, Roques BP, Campbell WB.) Endocrinology. 2018 Jan 01;159(1):238-247 PMID: 29088382 PMCID: PMC5761603 SCOPUS ID: 2-s2.0-85040728476 11/01/2017
Orally Active Epoxyeicosatrienoic Acid Analogs.
(Campbell WB, Imig JD, Schmitz JM, Falck JR.) J Cardiovasc Pharmacol. 2017 Oct;70(4):211-224 PMID: 28937442 PMCID: PMC5673125 SCOPUS ID: 2-s2.0-85032230771 09/25/2017
Vascular hepoxilin and trioxilins mediate vasorelaxation through TP receptor inhibition in mouse arteries.
(Siangjong L, Goldman DH, Kriska T, Gauthier KM, Smyth EM, Puli N, Kumar G, Falck JR, Campbell WB.) Acta Physiol (Oxf). 2017 Jan;219(1):188-201 PMID: 26666460 PMCID: PMC4909587 SCOPUS ID: 2-s2.0-84954478924 12/17/2015
Erratum: 14,15-epoxyeicosa-5,8,11-trienoic acid (14,15-EET) surrogates: Carboxylate modifications (Journal of Medicinal Chemistry (2014) 57 (6965-6972) DOI: 10.1021/jm500262m)
(Falck JR, Koduru SR, Mohapatra S, Manne R, Atcha KR, Manthati VL, Capdevila JH, Christian S, Imig JD, Campbell WB.) Journal of Medicinal Chemistry. 13 November 2014;57(21):9218 SCOPUS ID: 2-s2.0-84923793795 11/13/2014