EDUCATION AND EMPLOYMENT HISTORY
My research interest in cardiovascular disease started in 1998, when I was invited by Dr. Paul M. Vanhoutte, as an exchange scholar/student, to work with Dr. Chantal M. Boulanger at the Hôpital Lariboisiére in Paris, France. Two years later, I earned my Ph.D. in Cardiovascular Pharmacology at the Chinese Academy of Medical Sciences, the top one Medical University of China. Driven by my enthusiasm in the mechanisms of cardiovascular diseases (I also hold an M.D. in Clinical Medicine), I then undertook training as a Post-doctoral fellow and Research Associate (a faculty position) with Dr. Mordecai P. Blaustein at the University of Maryland School of Medicine. In 2008, I was appointed Assistant Professor in the Department of Physiology, University of Maryland School of Medicine, and in 2014, I was promoted to Associate Professor.
SELECTED HONORS & AWARDS
1995-1996: International Scholarship, Daiichi Pharmaceutical Co. Ltd., Japan.
2001-2003: Postdoctoral Fellowship Award, American Heart Association, USA.
2005: Symposium Award, Society of General Physiologists, USA.
2005: Travel Award, International Union of Physiological Sciences, USA.
2006: Pfizer Award, International Society of Hypertension.
2006: Young Investigator Travel Award, International Society of Hypertension.
2006: Young Investigator Award, Kidney and Hypertension, Japan
2007-2011: National Scientist Development Grant, American Heart Association, USA.
2008: Young Physiologists Symposium Award. Chinese Association of Physiological Sciences & American Physiological Society, China.
2010: Vancouver Hypertension Award, International Society of Hypertension, Canada.
Hypertension is a globally occurring type of incurable world spread disease that leads to end organ damage, e.g., stroke, cardiac and renal failure. The long-term goal of our research group has been to identify the molecular mechanisms that either contribute to or result from the development of hypertension.
My current research focuses on signaling mechanisms by which vascular smooth muscle-specific sodium/calcium exchanger (NCX) affect arterial contraction and blood pressure. Recent evidence reveals that vascular smooth muscle NCX1 is importantly involved in the control of arterial blood pressure in the normal state and in hypertension. In a paradigm shift, NCX1 is now conceived to be a key component of certain distinct signaling pathways that activate smooth muscle contraction in response to stretch (i.e. myogenic response), and to activation of certain G-protein coupled receptors. Thus, NCX1 is no longer conceived to be simply a "homeostatic housekeeper" molecule that keeps intracellular Ca2+ concentration low by extruding Ca2+. Rather, ion transport through NCX should be activated by specific physiological signals and mechanisms in vivo that control blood pressure. The crucial evidence for such activation is that blood pressure correlates with the level of NCX expression in vascular smooth muscle: knockout of NCX decreases blood pressure and arterial contractility, and over-expression increases blood pressure and salt-sensitivity in mice (see Publications below).
My research involves two inter-related areas: 1) to establish how the Ca2+ signaling pathway is altered in vascular smooth muscle cells of mice with altered amounts of NCX1, and its relationship to blood pressure change. 2) to investigate the molecular mechanisms that control arterial diameter in vivo by using exogenous FRET-based myosin light chain kinase (MLCK) biosensor mice that can report quantitative Ca2+ change in vascular smooth muscle cells in relation to blood pressure change. Thus, this research is able to: 1) characterize the details of vascular smooth muscle NCX1 in regulating intracellular Ca2+ in relation to small artery function and arterial blood pressure under normal physiological and pathological (e.g., hypertension) conditions; and 2) clarify the cellular mechanisms by which arterial NCX1 helps regulate intracellular Ca2+, MLCK activity, small artery function and blood pressure and, thus, to identify molecular targets for hypertension therapeutics.
Lab Techniques and Equipment:
A. Resistance small arterial handling (both in vivo and in vitro) from genetically engineered mice:
1) Mice with genetically altered expression of smooth muscle-specific NCX1 to reveal 'gain or lossâ?T of NCX1 function;
2) Biosensor mice that express genetically encoded smooth muscle or endothelium-specific Ca2+ indicator, GCaMP (Green Fluorescence Protein-coupled Ca2+/calmodulin probe), to permit high signal-to-noise optical recording of Ca2+ signaling (Ca2+ waves, Ca2+ sparks etc) in living cells of intact arteries or animals;
3) Biosensor mice that express a genetically encoded FRET type, Ca2+/calmodulin-sensitive exogenous MLCK (exMLCK) indicator molecule to allow quantitative measurement of intracellular Ca2+ concentration in individual cells within intact small arteries in vitro and in vivo.
B. Imaging techniques:
1) High resolution state-of-the-art digital 2D, as well as novel 3D and 4D, imaging in intact, pressurized small resistance arteries to monitor intracellular Ca2+ signaling changes during physiological stimuli, in vivo and in vitro, with laser scanning confocal fluorescence microscopy.
2) Quantitative intracellular Ca2+ concentration measurement in individual cells within intact small arteries, in vivo and in vitro, with wide-field epi-fluorescence microscopy and macroscopy equipped with multi-spectral cameras.
C. Long-term measurement of whole animal cardiovascular function, including survival surgery and telemetry.
Youhua Wang, Ph.D., Postdoctoral Fellow
Meng Li, M.D., Research Specialist
Helen Cha, Medical Student
Zhang J., Henrion D., Ebrahimian E.T., Benessiano J., Colucci-Guyon E., Langa F., Babinet C., Levy B. and Boulanger C.M. (2001) Increased contribution of the L-arginine nitric oxide pathway in the aorta of mice lacking the gene for the cytoskeleton protein vimentin. Journal of Cardiovascular Pharmacology, 38 (4): 552-560.
Zhang J., Wier W.G. and Blaustein M.P. (2002) Mg2+ blocks myogenic tone, but not K+-induced constriction: role for store-operated channels in small arteries. American Journal of Physiology Heart and Circulatory Physiology, 283: H2692-H2705.
Ji G., Feldman M.E., Deng K.Y., Green K.S., Wilson J., Lee J.C., Johnston R.C., Rishniw M., Tallini Y., Zhang J., Wier W.G., Blaustein M.P., Xin H.B., Nakai J. and Kotlikoff M.I. (2004) Ca2+-sensing transgenic mice: postsynaptic signaling in smooth muscle. Journal of Biological Chemistry, 279(20): 21461-21468.
Iwamoto T., Kita S., Zhang J., Blaustein M.P., Arai Y., Yoshida S., Wadimoto K., Komuro I. and Katsuragi T. (2004) Vascular Na+/Ca2+ exchanger type-1 is essential for the development of salt-sensitive hypertension. Nature Medicine, 10(11):1193-1199.
Blaustein M.P., Zhang J., Wier W.G. (2004) On the mechanism of myogenic tone in small arteries. Journal of Muscle Research and Cell Motility, 25(8): 615.
Zhang J., Lee MY., Cavalli M., Chen L., Berra-Romani R., Balke C. W., Bianchi G., Ferrari P., Hamlyn J.M., Iwamoto T., Lingrel J.B., Matteson D.R., Wier W.G. and Blaustein M.P. (2005) Sodium pump ï¡2 subunits control myogenic tone and blood pressure in mice. Journal of Physiology (London), 569: 243-256. PMCID: PMC1464198
Blaustein M.P., Zhang J., Chen L., Hamilton BP. (2006) How does salt retention raise blood pressure? American Journal of Physiology Regulatory, Integrative and Comparative Physiology (invited review) 290(3): R514-R523.
Zhang J., Berra-Romani R., Sinnegger-Brauns M. J., Striessnig J., Blaustein M. P. and Matteson D. R. (2007) Role of Cav1.2 L-type Ca2+ channels in vascular myogenic tone: effects of nifedipine and Mg2+. American Journal of Physiology Heart and Circulatory Physiology, 292(1): H415-H425.
Zacharia J., Zhang J., Wier W.G. (2007) Ca2+ signaling in mouse mesenteric small arteries: myogenic tone and adrenergic vasoconstriction. American Journal of Physiology Heart and Circulatory Physiology, 292(3): H1523-H1532.
Chen L., Zhang J., Gan T.X., Chen-Izu Y., Hasday J.D., Karmazyn M., Balke C.W., Scharf S.M. (2008) Left Ventricular Dysfunction and Associated Cellular Injury in Rats exposed to Chronic Intermittent Hypoxia. Journal of Applied Physiology, 104(1): 218-223.
Blaustein M.P., Zhang J., Chen L., Song H., Raina H., Kinsey S.P., Izuka M., Iwamoto T., Kotlikoff M.I., Lingrel J.B., Philipson K.D., Wier W.G., Hamlyn J.M. (2009) The pump, the exchanger and endogenous ouabain: signaling mechanisms that link salt retention to hypertension. Hypertension, 53(2): 291-298. (Novartis Award Invited Review). PMCID: PMC2727927
Zhang J., Hamlyn J.M., Karashima E., Mauban J. R.H., Izuka M., Berra-Romani R., Zulian A., Wier W.G., Blaustein M.P. (2009) Low Dose Ouabain Constricts Small Arteries from Ouabain-Hypertensive Rats: Implications for Sustained Elevation of Vascular Resistance. American Journal of Physiology Heart and Circulatory Physiology, 297(3): H1140-H1150. (First and corresponding author). PMCID: PMC2755988
Zhang J., Ren C.Y., Chen L., Navedo M.F., Antos L.K., Kinsey S., Iwamoto T., Philipson K.D., Kotlikoff M.I., Santana LF, Wier WG, Matteson D.R., Blaustein M.P. (2010) Knockout of Na/Ca Exchanger in smooth muscle attenuates vasoconstriction and L-type voltage channel current and lowers blood pressure. American Journal of Physiology Heart and Circulatory Physiology, 298(5): H1472-1483. (First and corresponding author). PMCID: PMC2867439
Ren C.Y., Zhang J., Philipson K.D., Kotlikoff M.I., Blaustein M.P., Matteson D.R. (2010) Activation of L-type Ca2+ channels by protein kinase C is reduced in smooth muscle specific Na+/Ca2+ exchanger knockout mice. American Journal of Physiology Heart and Circulatory Physiology, 298(5): H1484-1491. PMCID: PMC2867443
Zhang J., Chen L., Blaustein M.P., Wier W.G. (2010) In vivo measurement of arterial pressure, [Ca2+] and MLCK activation in FRET-based biosensor mice. American Journal of Physiology Heart and Circulatory Physiology. 299(3): H946-956. (First and corresponding author). PMCID: PMC2944472
Chen L., Zhang J., Hu X., Philipson K.D., Scharf SM. (2010) The Na+/Ca2+ exchanger-1 mediates left ventricular dysfunction in mice with chronic intermiitent hypoxia. Journal of Applied Physiology, 109(6): 1675-1685. PMCID: PMC3006405
Xu K.Y., Zhu W.Z., Chen L., DeFilippi C., Zhang J., Xiao R. P. (2011) Mechanistic distinction between activation and inhibition of (Na++K+)-ATPase-mediated Ca2+ influx in cardiomyocytes. Biochemical and Biophysical Research Communications. 406(2): 200-3. PMCID: PMC3066659
Zhao D., Zhang J., Blaustein M. P., Navar G. (2011) Attenuated renal vascular responses to acute angiotensin II infusion in smooth muxscle-specific Na+/Ca2+ exchanger knockout mice. American Journal of Physiology Renal Physiology. 301(3): F574-579. PMCID: PMC3174546
Blaustein M.P., Leenen F.H.H, Chen L., Golovina V.A., Hamlyn J.M., Pallone T.L2,3, Van Huysse J.W., Zhang J. and Wier W.G. (2012) How NaCl raises blood pressure: A new paradigm for the pathogenesis of salt-dependent hypertension. American Journal of Physiology Heart and Circulatory Physiology. 302(5):H1031-49. PMCID: PMC3311458
Mauban J. R.H., Zacharia J., Zhang J., Wier W.G. (2013) Vascular tone and Ca2+ signaling in murine cremaster muscle arterioles in vivo. Microcirculation. 20(3):269-277. PMCID: PMC4019383.
Zhang J. (2013) New insights into the contribution of arterial NCX to the regulation of myogenic tone and blood pressure. Advances in Experimental Medicine and Biology. 961:329-343.
Wang Y, Chen L, Wier WG, Zhang J. (2013) Intravital FRET imaging reveals elevated [Ca2+]i and enhanced sympathetic tone in femoral arteries of angiotensin II-infused hypertensive biosensor mice. Journal of Phyiology (London). 591(21): 5321-5336. 2013. PMCID: PMC3936370. [This paper has received a Perspective Highlight. Hill M.A. Meininger G.A. Should we be sympathetic to angiotensin II infusion? Journal of Physiology (London). 591(21): 5269-5270. 2013. PMCID: PMC3936364.]
Mauban J. R.H., Fairfax S., Rizzo M., Zhang J., Wier W.G. (2014) A method for non-invasive longitudinal measurements of [Ca2+] in small arteries and arterioles of hypertensive optical biosensor mice. American Journal of Physiology Heart and Circulatory Physiology. 2014. [EPub ahead of Print]. PMCID: PMC in process.
Fairfax S., Mauban J. R.H., Hao S., Rizzo M., Zhang J., Wier W.G. (2014) Ca2+ signaling in arterioles and small arteries of conscious optical biosensor mice. Frontiers in Physiology. 2014. (Submitted).