Meredith Hay

Meredith Hay

Professor, Physiology
Professor, Evelyn F Mcknight Brain Institute
Professor, Psychology
Professor, Physiological Sciences - GIDP
Professor, BIO5 Institute
Primary Department
Department Affiliations
Contact
(520) 626-7384

Work Summary

Our lab is focused on the development of novel peptides to inhibit this inflammatory cascade and improve brain blood flow. These peptides are designed to significantly improve serum half-life and penetrate the blood-brain-barrier. These peptides act to inhibit the inflammatory pathways at both the level of brain blood vessels and the brain itself.

Research Interest

Dr. Hay is internationally known for her work in cardiovascular neurobiology and her current studies on the role of sex and sex hormones in the development of hypertension. She has been continuously funded by the NIH and other sources for the past 26 years. She has extensive experience in central renin angiotensin mechanisms, neurophysiology and reactive oxygen and cytosolic calcium neuroimaging and in advancing knowledge related to central mechanisms of neurohumoral control of the circulation. She is a Professor of Physiology at the University of Arizona College of Medicine and maintains active participation in the American Physiological Society, the Society of Neuroscience, AAAS, and has served on numerous editorial boards of prestigious scientific journals and grant review panels for the National Institutes of Health and the National American Heart Association. The primary focus of Dr. Hay’s laboratory is the understanding of the biophysical and cellular mechanisms underlying neurotransmitter modulation of sympathetic outflow and ultimately arterial blood pressure. The scientific questions being asked are: 1) What central neurotransmitter mechanisms are involved in the normal regulation of cardiovascular function? 2) Does the development of some forms of hypertension involve biophysical or molecular alteration in the neurotransmitter mechanisms regulating cardiovascular control? 3) Can these central signal transduction systems, which control sympathetic outflow and ultimately arterial blood pressure, be altered in order to prevent or attenuate the development of some forms of hypertension? 4) Are there gender related differences in some of these mechanisms?Dr. Hay has extensive national experience in university-wide administration and interdisciplinary research program development. Prior to coming to the University of Arizona in 2008 as Executive Vice President and Provost, Dr. Hay was the Vice President for Research for the University of Iowa, where she worked with state and federal lawmakers, private sector representatives, and local community groups to broaden both private and public support for research universities. Dr. Hay, a Texas native, earned her B.A. in psychology from the University of Colorado, Denver, her M.S. in neurobiology from the University of Texas at San Antonio, and her Ph.D. in cardiovascular pharmacology from the University of Texas Health Sciences Center, San Antonio. She trained as a postdoctoral fellow in the Cardiovascular Center at the University of Iowa College of Medicine and in the Department of Molecular Physiology and Biophysics at Baylor College of Medicine in Houston. She was a tenured faculty member of the University of Missouri-Columbia from 1996-2005. Prior to Missouri, she was a faculty member in the Department of Physiology at the University of Texas Health Science Center- San Antonio.

Publications

Pamidimukkala, J., & Hay, M. (2003). 17 beta-Estradiol inhibits angiotensin II activation of area postrema neurons. American journal of physiology. Heart and circulatory physiology, 285(4), H1515-20.

It is well established that the area postrema, as a circumventricular organ, is susceptible to modulation by circulating hormones and peptides. Furthermore, activation of the area postrema has been shown to modulate central neurons involved in the regulation of cardiovascular function and blood pressure. In particular, the vasoactive peptide angiotensin II (ANG II) has been shown to inhibit baroreflex regulation of heart rate and increase sympathetic outflow and blood pressure via activation of area postrema neurons. Estrogen is thought to protect against hypertension in both humans and animal models and has been shown in a number of systems to alter the effects of ANG II. The purpose of the present study was to determine the effects of estrogen on ANG II activation of area postrema neurons. In this study, the effects of ANG II and KCl on fura 2-measured cytosolic Ca2+ concentration ([Ca2+]i) responses in cultured area postrema neurons in the presence and absence of 12-h exposure to 100 nM 17 beta-estradiol (E2) were evaluated. In neurons incubated in control vehicle media, 50 nM ANG II increased [Ca2+]i by 92 +/- 12%. In neurons preincubated with 100 nM E2, ANG II increased [Ca2+]i by only 68 +/- 11%, for a total inhibition of the ANG II-evoked response of 24%. Coapplication of the estrogen receptor antagonist ICI-182,780 did not inhibit the effects of E2. In the same cells in which the effects of E2 on ANG II-evoked responses were tested, the effects of incubation in E on the depolarization-induced increased [Ca2+2]i due to 60 mM KCl were also tested. Incubation of the cells with 100 nM E increased the KCl-evoked [Ca2+2]i response, and this response was blocked by ICI-182,780. These results suggest that in the area postrema, estrogen may utilize multiple pathways to modulate neural activity and responses to ANG II.

Xue, B., Zhang, Z., Johnson, R. F., Guo, F., Hay, M., & Johnson, A. K. (2013). Central endogenous angiotensin-(1-7) protects against aldosterone/NaCl-induced hypertension in female rats. American journal of physiology. Heart and circulatory physiology, 305(5), H699-705.

In comparison to male rodents, females are protected against angiotensin (ANG) II- and aldosterone (Aldo)-induced hypertension. However, the mechanisms underlying this protective effect are not well understood. ANG-(1-7) is formed from ANG II by angiotensin-converting enzyme 2 (ACE2) and has an antihypertensive effect in the central nervous system (CNS). The present study tested the hypothesis that central ANG-(1-7) plays an important protective role in attenuating the development of Aldo/NaCl-hypertension in female rats. Systemic infusion of Aldo into intact female rats with 1% NaCl as their sole drinking fluid resulted in a slight increase in blood pressure (BP). Intracerebroventricular (icv) infusion of A-779, an ANG-(1-7) receptor (Mas-R) antagonist, significantly augmented the pressor effects of Aldo/NaCl. In contrast, systemic Aldo/NaCl induced a significant increase in BP in ovariectomized (OVX) female rats, and central infusion of ANG-(1-7) significantly attenuated this Aldo/NaCl pressor effect. The inhibitory effect of ANG-(1-7) on the Aldo/NaCl pressor effect was abolished by concurrent infusion of A-779. RT-PCR analyses showed that there was a corresponding change in mRNA expression of several renin-angiotensin system components, estrogen receptors and an NADPH oxidase subunit in the lamina terminalis. Taken together these results suggest that female sex hormones regulate an antihypertensive axis of the brain renin-angiotensin system involving ACE2/ANG-(1-7)/Mas-R that plays an important counterregulatory role in protecting against the development of Aldo/NaCl-induced hypertension.

Xue, B., Zhao, Y., Johnson, A. K., & Hay, M. (2008). Central estrogen inhibition of angiotensin II-induced hypertension in male mice and the role of reactive oxygen species. American journal of physiology. Heart and circulatory physiology, 295(3), H1025-H1032.

It has been shown that reactive oxygen species (ROS) contribute to the central effect of ANG II on blood pressure (BP). Recent studies have implicated an antihypertensive action of estrogen in ANG II-infused female mice. The present study used in vivo telemetry recording and in vitro living mouse brain slices to test the hypothesis that the central activation of estrogen receptors in male mice inhibits ANG II-induced hypertension via the modulation of the central ROS production. In male wild-type mice, the systemic infusion of ANG II induced a significant increase in BP (Delta30.1 +/- 2.5 mmHg). Either central infusion of Tempol or 17beta-estradiol (E2) attenuated the pressor effect of ANG II (Delta10.9 +/- 2.3 and Delta4.5 +/- 1.4 mmHg), and the protective effect of E2 was prevented by the coadministration of an estrogen receptor, antagonist ICI-182780 (Delta23.6 +/- 3.1 mmHg). Moreover, the ganglionic blockade on day 7 after the start of ANG II infusions resulted in a smaller reduction of BP in central Tempol- and in central E2-treated males, suggesting that estrogen inhibits the central ANG II-induced increases in sympathetic outflow. In subfornical organ slices, the application of ANG II resulted in a 21.5 +/- 2.5% increase in ROS production. The coadministration of irbesartan, an ANG II type 1 receptor antagonist, or the preincubation of brain slices with Tempol blocked ANG II-induced increases in ROS production (-1.8 +/- 1.6% and -1.0 +/- 1.8%). The ROS response to ANG II was also blocked by E2 (-3.2 +/- 2.4%). The results suggest that the central actions of E2 are involved in the protection from ANG II-induced hypertension and that estrogen modulation of the ANG II-induced effects may involve interactions with ROS production.

Forte, B. L., Slosky, L. M., Zhang, H., Arnold, M. R., Staatz, W. D., Hay, M., Largent-Milnes, T. M., & Vanderah, T. W. (2016). Angiotensin-(1-7)/Mas receptor as an antinociceptive agent in cancer-induced bone pain. Pain, 157(12), 2709-2721.
BIO5 Collaborators
Meredith Hay, Tally M Largent-Milnes

Many cancerous solid tumors metastasize to the bone and induce pain (cancer-induced bone pain [CIBP]). Cancer-induced bone pain is often severe because of enhanced inflammation, rapid bone degradation, and disease progression. Opioids are prescribed to manage this pain, but they may enhance bone loss and increase tumor proliferation, further compromising patient quality of life. Angiotensin-(1-7) (Ang-(1-7)) binds and activates the Mas receptor (MasR). Angiotensin-(1-7)/MasR activation modulates inflammatory signaling after acute tissue insult, yet no studies have investigated whether Ang-(1-7)/MasR play a role in CIBP. We hypothesized that Ang-(1-7) inhibits CIBP by targeting MasR in a murine model of breast CIBP. 66.1 breast cancer cells were implanted into the femur of BALB/cAnNHsd mice as a model of CIBP. Spontaneous and evoked pain behaviors were assessed before and after acute and chronic administration of Ang-(1-7). Tissues were collected from animals for ex vivo analyses of MasR expression, tumor burden, and bone integrity. Cancer inoculation increased spontaneous pain behaviors by day 7 that were significantly reduced after a single injection of Ang-(1-7) and after sustained administration. Preadministration of A-779 a selective MasR antagonist prevented this reduction, whereas pretreatment with the AT2 antagonist had no effect; an AT1 antagonist enhanced the antinociceptive activity of Ang-(1-7) in CIBP. Repeated Ang-(1-7) administration did not significantly change tumor burden or bone remodeling. Data here suggest that Ang-(1-7)/MasR activation significantly attenuates CIBP, while lacking many side effects seen with opioids. Thus, Ang-(1-7) may be an alternative therapeutic strategy for the nearly 90% of patients with advanced-stage cancer who experience excruciating pain.

Hay, M., & Lindsley, K. A. (1995). Membrane properties of area postrema neurons. Brain research, 705(1-2), 199-208.

Intrinsic membrane properties, voltage-dependent sodium and voltage-dependent potassium currents of area postrema neurons in culture have been characterized with respect to their voltage dependence, time dependence and sensitivity to specific blocking agents. The area postrema is a hindbrain circumventricular organ which is known to have an important role in the central regulation of cardiovascular function. This study is the first to describe the biophysical properties of ion channels present in rat area postrema neurons. Recordings in current-clamp mode revealed a mean resting membrane potential of -55.0 +/- 1.6 (n = 24) mV and an input resistance of 213.6 +/- 23 M omega. For the 24 neurons tested, the evoked action potential had a mean threshold of 38.8 +/- 2 mV and a mean amplitude of 107.3 +/- 15 mV. Our results show that the area postrema possesses only one principle sodium current which is completely abolished by 5 microM tetrodotoxin (TTX) (n = 28). This current activated near -50 mV and reached peak amplitude at -30 mV. The area postrema does not possess a TTX insensitive sodium current. The area postrema has at least two types of potassium currents. All area postrema neurons studied with tetraethylamonium (TEA) (n = 40) showed the presence of a slowly activating outward current which was present at voltages greater than -40 mV and was blocked by 10 mM TEA. In addition, 75% of the neurons studied (n = 30/40) also showed a rapidly inactivating, 4-AP sensitive IA type current which activated near -30 mV. Angiotensin II attenuated both the peak and the steady-state potassium currents, suggesting that angiotensin II may modulate area postrema activity by inhibiting voltage-gated potassium channels.