Sandra L. Pfister, PhD
- Pharmacology and Toxicology
BS, St. Mary's University, San Antonio, TX, 1978
- Chair Emeritus, Council for Women's Advocacy
- Course Director, M2 Cardiovascular Unit
- Course Director, Principles of Drug Action
- Member Faculty Pillar, Kern Institute
- Vice-President, Faculty Council
Sex, Vascular Tone and Arachidonic Acid Metabolism
Pulmonary arterial hypertension (PAH) is a devastating disease characterized by a progressive increase in pulmonary vascular resistance that if untreated results in right ventricular failure and death. Despite major therapeutic advances in the last decade, there is no cure for this disease. Recent evidence showed that the female-to-male ratio in the incidence of PAH has increased from 1.7:1 in the 1980’s to 4.1:1 in 2007. This is an alarming statistic that needs to be addressed experimentally. Mechanisms to explain the female predominance are scarce but likely relate to changes in estrogen that contribute to the pathogenesis of the disease. While the human data predicts that estrogen contributes to disease progression, studies in many animal models reported that estrogen was protective and decreased the severity of PAH. Because of these inconsistencies, our laboratory developed a different experimental approach and showed in a rabbit model without any manipulations to elicit PAH that there are sex-based differences in pulmonary artery vasoconstriction attributable to 15-hydroxyeicosatrienoic acid (HETE). 15-HETE is a 15-lipoxygenase (LO) metabolite of the arachidonic acid pathway. Our data showed that females had increased expression of 15-LO, increased production of 15-HETE and increased sensitivity to 15-HETE-mediated vasoconstriction compared to males. Equally exciting were results that showed that estrogen treatment of male pulmonary arteries increased 15-LO expression and 15-HETE production. Specific studies are designed to define the mechanisms that explain the interaction of estrogen and 15-HETE and how these mechanisms contribute to female predominance in PAH. Experiments address the hypothesis that the increased pulmonary artery vasoconstriction in females compared to males is due to a unique combination of mechanisms: 1) estrogen modulation of 15-LO expression via activation of the cytokine signal transducer and activator of transcription pathway and 2) increased 15-HETE sensitivity due to increased inhibition of voltage-gated potassium channels and/or increased 15-HETE receptor expression. Identifying the described mechanisms will likely provide new insights into female predominance in PAH and lead to new options for treatments.
Thromboxane Receptors in Atherosclerosis
More than 90 million Americans have elevated blood cholesterol and an increased likelihood of developing atherosclerosis. The overall goal of our research is to explore novel mechanisms that contribute to atherosclerosis. Of particular interest to our laboratory is evidence that the synthesis of thromboxane, a metabolite of arachidonic acid in platelets, increases in atherosclerosis, and blockade of thromboxane receptors attenuates atherosclerotic plaque formation. The current therapeutic strategy of low dose aspirin to protect against cardiovascular disease provides further evidence that thromboxane is an important component of the vascular responses in atherosclerosis since this regimen is designed to selectively inhibit platelet thromboxane production. While it is well established that thromboxane promotes both platelet aggregation and vascular smooth muscle vasoconstriction, the exact role of vascular and platelet thromboxane receptor activation in the development and progression of atherosclerosis remains unclear. Our previous work identified a subgroup of rabbits deficient in vascular but not platelet thromboxane receptors. Our research examines the overall objective that the vascular thromboxane receptor plays a role in the pathogenesis of atherosclerosis that is distinct from the role of the platelet thromboxane receptor. The central hypothesis is that an absence of vascular thromboxane receptors delays the development and progression of atherosclerosis resulting in preserved endothelial function. Studies are designed 1) to evaluate the development and progression of atherosclerosis in rabbits with and without vascular thromboxane receptors, 2) to investigate the hypothesis that activation of endothelial thromboxane receptors contributes to the pathogenesis of atherosclerosis, and 3) to examine the role of the platelet thromboxane receptor in the pathogenesis of atherosclerosis. The further understanding of the role of vascular and platelet thromboxane receptors in the pathogenesis of atherosclerosis as outlined by this proposal will allow the development of future therapeutic treatments.
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
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
(5Z,11Z,15R)-15-Hydroxyeicosa-5,11-dien-13-ynoic acid: A stable isomer of 15(S)-HETE that retains key vasoconstrictive and antiproliferative activity.
(Pfister SL, Klimko PG, Conrow RE.) Prostaglandins Other Lipid Mediat. 2016 Mar;123:33-9 PMID: 27117058 PMCID: PMC4893888 SCOPUS ID: 2-s2.0-84969584659 04/28/2016
Tyrosine dephosphorylation enhances the therapeutic target activity of epidermal growth factor receptor (EGFR) by disrupting its interaction with estrogen receptor (ER).
(Ma S, Yin N, Qi X, Pfister SL, Zhang MJ, Ma R, Chen G.) Oncotarget. 2015 May 30;6(15):13320-33 PMID: 26079946 PMCID: PMC4537017 SCOPUS ID: 2-s2.0-84931073824 06/17/2015
Endothelial 12(S)-HETE vasorelaxation is mediated by thromboxane receptor inhibition in mouse mesenteric arteries.
(Siangjong L, Gauthier KM, Pfister SL, Smyth EM, Campbell WB.) Am J Physiol Heart Circ Physiol. 2013 Feb 01;304(3):H382-92 PMID: 23203967 PMCID: PMC3774504 SCOPUS ID: 2-s2.0-84873319463 12/04/2012
Pulmonary arterial responses to reactive oxygen species are altered in newborn piglets with chronic hypoxia-induced pulmonary hypertension.
(Fike CD, Aschner JL, Slaughter JC, Kaplowitz MR, Zhang Y, Pfister SL.) Pediatr Res. 2011 Aug;70(2):136-41 PMID: 21516056 PMCID: PMC3131458 04/26/2011
Role of superoxide and thromboxane receptors in acute angiotensin II-induced vasoconstriction of rabbit vessels.
(Pfister SL, Nithipatikom K, Campbell WB.) Am J Physiol Heart Circ Physiol. 2011 Jun;300(6):H2064-71 PMID: 21460202 PMCID: PMC3119100 SCOPUS ID: 2-s2.0-79958028562 04/05/2011
Role of lipoxygenase metabolites of arachidonic acid in enhanced pulmonary artery contractions of female rabbits.
(Pfister SL.) Hypertension. 2011 Apr;57(4):825-32 PMID: 21300669 PMCID: PMC3073701 SCOPUS ID: 2-s2.0-79953224393 02/09/2011
Mechanisms underlying increased reactivity of pulmonary arteries contralateral to a localized high-flow anastomosis.
(Pfister S, Somberg L, Lowry T, Gao Y, Medhora M, Jacobs ER.) J Thorac Cardiovasc Surg. 2011 Feb;141(2):425-31 PMID: 21075383 PMCID: PMC3052931 SCOPUS ID: 2-s2.0-78751601116 11/16/2010
Protein complex formation with heat shock protein 90 in chronic hypoxia-induced pulmonary hypertension in newborn piglets.
(Fike CD, Pfister SL, Slaughter JC, Kaplowitz MR, Zhang Y, Zeng H, Frye NR, Aschner JL.) Am J Physiol Heart Circ Physiol. 2010 Oct;299(4):H1190-204 PMID: 20693398 PMCID: PMC2957352 SCOPUS ID: 2-s2.0-77958025198 08/10/2010
Vascular pharmacology of epoxyeicosatrienoic acids.
(Pfister SL, Gauthier KM, Campbell WB.) Adv Pharmacol. 2010;60:27-59 PMID: 21081214 PMCID: PMC3373307 SCOPUS ID: 2-s2.0-78349236168 11/18/2010
Chronic hypoxia enhances 15-lipoxygenase-mediated vasorelaxation in rabbit arteries.
(Aggarwal NT, Pfister SL, Gauthier KM, Chawengsub Y, Baker JE, Campbell WB.) Am J Physiol Heart Circ Physiol. 2009 Mar;296(3):H678-88 PMID: 19112096 PMCID: PMC2660232 SCOPUS ID: 2-s2.0-64049085636 12/30/2008