BIOGRAPHICAL SKETCH. POSITION TITLE: Professor of Medical Physiology; Director of MPHY Division of Vascular Biology

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1 OMB No and (Rev. 10/15 Approved Through 10/31/2018) NAME: Cynthia J. Meininger BIOGRAPHICAL SKETCH era COMMONS USER NAME (credential, e.g., agency login): POSITION TITLE: Professor of Medical Physiology; Director of MPHY Division of Vascular Biology EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.) Completion DEGREE INSTITUTION AND LOCATION Date FIELD OF STUDY (if applicable) MM/YYYY University of South Florida, Tampa, FL B.A. 06/1980 Cell Biology Texas A&M University, College Station, TX Ph.D. 05/1987 Vascular Cell Biology Texas A&M University, College Station, TX Postdoc 05/1989 Vascular Cell Biology A. Personal Statement I was trained as a cell biologist, with specialty training in vascular cell biology. I have spent over 30 years studying endothelial cell function, with an initial focus on physiological control of angiogenesis (i.e., endothelial cell migration and proliferation). I am happy to assist other investigators in isolating, propagating and studying endothelial cells. Early in my career, I developed an interest in mast cells and studied their role in modulating the vascularization and growth of tumors, including hemangiomas, the most extreme example of angiogenesis [a hemangioma is a tumor composed of blood vessels]. Interestingly, endothelial cells in blood vessels and mast cells that surround blood vessels exhibit a bi-directional relationship endothelial cells release stem cell factor (SCF), which attracts mast cells and, at high enough concentrations, can induce mast cell degranulation. Mast cells, on the other hand, release mediators that affect endothelial migration and proliferation. Indeed, we found that breast cancer cells overexpressing SCF attracted more mast cells to the tumor and subsequently exhibited increased endothelial cell density within the tumors. In collaboration with Dr. Heather Francis, a novel role was found for mast cell histamine in the progression of liver cancer. As an endothelial cell biologist, I have also been interested in the biology of lymphatic endothelial cells. I have collaborated with Anatoliy Gashev on studies to investigate the mechanisms of functional interactions of mesenteric lymphatic vessels and mast cells. Finally, I demonstrated that the enzymatic cofactor tetrahydrobiopterin is deficient in endothelial cells, reducing nitric oxide production and contributing to vascular dysfunction in diabetes. Current research in my lab is directed at developing solid lipid nanoparticles to selectively deliver tetrahydrobiopterin via the gastrointestinal lymphatics in order to normalize blood vascular endothelial levels of this critical co-factor and potentially prevent vascular complications of diabetes caused by reduced nitric oxide bioavailability. B. Positions and Honors Positions and Employment Graduate Teaching Asst, Dept of Biology, Texas A&M Univ, College Station, TX Graduate Research Asst, Dept of Medical Physiology, Texas A&M, College Station, TX Postdoctoral Res Assoc, Dept of Medical Physiology, Texas A&M, College Station, TX Postdoctoral Fellow, Dept of Medical Physiology, Texas A&M Univ, College Station, TX Asst Research Scientist, Dept of Medical Physiology, Texas A&M, College Station, TX Visiting Asst Professor, Dept of Surgery, Harvard Medical School, Boston, MA Asst Professor, Dept of Medical Physiology, Texas A&M HSC, College Station, TX Assoc Professor, Dept of Med Physiology, Texas A&M HSC, College Station, TX 2006 Assoc Professor, Dept of Systems Biology and Translational Medicine, Texas A&M HSC, College Station/Temple, TX 2006-pres. Professor, Dept of Systems Biology and Translational Medicine, Texas A&M Health Science Center, College Station/Temple, TX 2006-pres. Director, Vascular Biology Division, Cardiovascular Research Institute, Texas A&M Health Science Center, College Station/Temple, TX

2 2010-pres pres. Director of Graduate Studies, Texas A&M Health Science Center, Temple Campus, Temple, TX Associate Director, MD/PD Program, Texas A&M Health Science Center, Temple Campus, Temple, TX Other Experience and Professional Service/ships Fulbright Scholar Program, Council for International Exchange of Scholars, Life Sciences: Biochemical 2 Review Committee 2015 Florida Dept. of Health James & Esther King Biomedical Research Program, Ad Hoc Reviewer Pennsylvania Department of Health/Oak Ridge Associated Universities, Ad Hoc Reviewer American Heart Association, SouthWest Affiliate, Research Advisory Committee National Medical Research Council of Singapore, Research Grant Program Ad Hoc Reviewer 2013 New Zealand Ministry of Health of Science and Innovation, Ad Hoc Grant Reviewer 2012 National Institutes of Health Special Emphasis Review Panel ZDK1-GRB-S, P30 Diabetes Research Centers, National Institute of Diabetes and Digestive and Kidney Diseases 2012 Diabetes U.K. Project Grants, The British Diabetic Association, Ad Hoc Reviewer 2011 National Institutes of Health, Type 1 Diabetes Impact Award (DP3) Panel, National Institute of Diabetes and Digestive and Kidney Diseases American Heart Association, Vascular Biology and Blood Pressure/Regulation Study Section American Heart Association, Summer Undergraduate Research Fellowship Study Section 2011 American Heart Association, Medical Student Research Fellowship Review Panel 2010 National Institutes of Health, National Heart Lung and Blood Institute, Program Project Review Panel 2010 Wellcome Trust, Molecules, Genes and Cells Grant Review, Ad Hoc Reviewer National Institutes of Health, National Heart Lung and Blood Institute, Vascular Cell and Molecular Biology Study Section, Ad Hoc 2009 National Aeronautics and Space Administration, Fundamental Space Biology: Animal Cell Study Section 2008 National Institutes of Health, Type I Diabetes Pathfinder Grant Review Panel, NIDDK 2007 National Institutes of Health, Vascular Biology Special Emphasis Panel of the Cardiovascular Sciences, NHLBI 2007 National Institutes of Health, Special Emphasis Panel Review of Diabetes Endocrinology Research Centers (DERCs) and Diabetes Research and Training Centers (DRTCs), NIDDK 2007 National Institutes of Health, Vascular Cell and Molecular Biology Study Section, Ad Hoc Council for International Exchange of Scholars (Fulbright Scholar Program), Life Sciences C Biochemical Specialist Review Committee Microcirculatory Society, President ( ); President-Elect ( ) American Heart Association, Vascular Biology and Blood Pressure/Regulation Study Section Tetrahydrobiopterin Cardiovascular Advisory Board, Biomarin Pharmaceuticals American Heart Association, Texas Affiliate, Research Allocations and Advisory Committee National Medical Research Council, Singapore, Ad Hoc Grant Reviewer Microcirculatory Society, Secretary American Heart Association, Western States Affiliate, Lipid Metabolism, Thrombosis and Vascular Wall Biology Study Section (Chair ; Co-Chair ) Editorial Board : Microcirculation National Aeronautics and Space Administration:, Cell and Molecular Biology; Cell Biotechnology; and Integrative Physiology Study Sections National Institutes of Health, Clinical Studies Subcommittee D, Program Project Initial Review Group, National Cancer Institute 2004 National Institutes of Health,, RFA Study Section (Progression of Cardiovascular Disease in Type I Diabetes), National Heart, Lung and Blood Institute 2004 American Institute of Biological Sciences, Ad Hoc Grant Reviewer 1999 Veterans Administration Merit Awards, Respiratory Subcommittee, Ad Hoc Reviewer American Heart Association, Lung, Resuscitation, and Respiration Study Section

3 Honors/Awards 2017 Academy of Distinguished Medical Educators, Texas A&M University Health Science Center 2015 Distinguished Achievement Award, Texas A&M University Association of Former Students 2013 Most Outstanding Professor, Graduate Student Symposium, Texas A&M Health Science Center 2011 Outstanding Graduate Mentor Award, Texas A&M HSC, School of Graduate Studies 1989 International Union of Physiological Sciences Travel Award National Research Service Award, National Institutes of Health, NHLBI National Institutes of Health, Cooperative Education Program Participant C. Contributions to Science (1) Metabolic control of blood vessel growth. I began my research career studying angiogenesis, the growth of blood vessels, with a focus on the signals that regulate this process in the context of metabolic control of the tissue environment. I demonstrated the ability of hypoxia as well as adenosine, a metabolite of hypoxia, to stimulate endothelial cell migration and proliferation, the foundation of the angiogenic process. This was a significant contribution to our knowledge of cell signaling in general and angiogenesis in particular, as it pre-dated the discovery and characterization of the hypoxia-inducible factor 1 (HIF-1) transcription factor that regulates over 40 genes and is now known to regulate angiogenesis via the production of vascular endothelial growth factor (VEGF). HIF1, via its control of VEGF and other factors, plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease. My work helped to shape our understanding of the cellular and systemic homeostatic response to hypoxia in the tissue. a) Meininger CJ, Schelling ME, Granger HJ. Adenosine and hypoxia stimulate proliferation and migration of endothelial cells. Am J Physiol Sep;255(3 Pt 2):H PMID: b) Meininger CJ, Granger HJ. Mechanisms leading to adenosine-stimulated proliferation of microvascular endothelial cells. Am J Physiol Jan;258(1 Pt 2):H PMID: (2) Role for mast cells in angiogenesis/lymphatic biology. Early in my career, I developed an interest in mast cells and studied their role in modulating the vascularization and growth of tumors, including hemangiomas, the most extreme example of angiogenesis [a hemangioma is a tumor composed of blood vessels]. Interestingly, endothelial cells in blood vessels and mast cells that surround blood vessels exhibit a bi-directional relationship endothelial cells release stem cell factor (SCF), which attracts mast cells and, at high enough concentrations, can induce mast cell degranulation. Mast cells, on the other hand, release mediators that affect endothelial migration and proliferation (i.e., angiogenesis). Indeed, we found that breast cancer cells overexpressing SCF attracted more mast cells to the tumor and subsequently exhibited increased endothelial cell density (i.e., angiogenesis) within the tumors. In more recent collaborations, we demonstrated a novel role for mast cell histamine in the progression of liver cancer and are currently investigating the role of mast cells and their products in regulating lymphatic function. a) Meininger CJ, Yano H, Rottapel R, Bernstein A, Zsebo KM, Zetter BR. The c-kit receptor ligand functions as a mast cell chemoattractant. Blood Feb 15;79(4): PMID: b) Meininger CJ, Brightman SE, Kelly KA, Zetter BR. Increased stem cell factor release by hemangioma derived endothelial cells. Lab Invest Feb;72(2): PMID: c) Zhang W, Stoica G, Tasca SI, Kelly KA, Meininger CJ. Modulation of tumor angiogenesis by stem cell factor. Cancer Res Dec 1;60(23): PMID: d) Nizamutdinova IT, Maejima D, Nagai T, Bridenbaugh E, Thangaswamy S, Chatterjee V, Meininger CJ, Gashev AA. Involvement of histamine in endothelium-dependent relaxation of mesenteric lymphatic vessels. Microcirculation Oct;21(7): doi: /micc PMID: ; PMCID: PMC e) Nizamutdinova IT, Dusio GF, Gasheva OY, Skoog H, Tobin R, Peddaboina C, Meininger CJ, Zawieja DC, Newell-Rogers MK, Gashev AA. Mast cells and histamine are triggering the NF-kB-mediated reactions of adult and aged perilymphatic mesenteric tissues to acute inflammation. Aging (11): doi: /aging PMID: ; PMCID: PMC f) Tsoy Nisamutdinova I, Maejima D, Nagai T, Meininger CJ, Gashev AA. Histamine as an endotheliumderived relaxing factor in aged mesenteric lymphatic vessels. Lymphat Res Biol doi: /lrb PMID:

4 (3) Lymphatic endothelial cell biology. Endothelial cells line lymphatic vessels, just as they do blood vessels, but the studies characterizing lymphatic endothelial cells and their role in controlling lymphatic function have significantly lagged behind those of the blood vasculature. I have worked out protocols to isolate and culture lymphatic endothelial cells for collaborators, allowing study of their structure and function. a) Hayes H, Kossmann E, Wilson E, Meininger C, Zawieja D. Development and characterization of endothelial cells from rat microlymphatics. Lymphat Res Biol. 2003;1(2): PMID: b) Gashev AA, Davis MJ, Gasheva OY, Nepiushchikh ZV, Wang W, Dougherty P, Kelly KA, Cai S, Von Der Weid PY, Muthuchamy M, Meininger CJ, Zawieja DC. Methods for lymphatic vessel culture and gene transfection. Microcirculation Oct;16(7): doi: / PMID: ; PMCID: PMC (4) Tetrahydrobiopterin deficiency and endothelial function. My work as an endothelial cell biologist took a turn when I began a collaboration to examine the vascular complications of diabetes. We demonstrated that endothelial cells in diabetic rats displayed a deficiency in the enzymatic co-factor tetrahydrobiopterin and this was responsible for reducing the bioavailability of nitric oxide and causing dysfunction of endothelial cells, the first step in the development of atherosclerosis. a) Meininger CJ, Marinos RS, Hatakeyama K, Martinez-Zaguilan R, Rojas JD, Kelly KA, Wu G. Impaired nitric oxide production in coronary endothelial cells of the spontaneously diabetic BB rat is due to tetrahydrobiopterin deficiency. Biochem J Jul 1;349(Pt 1): PMID: ; PMCID: PMC b) Marinos RS, Zhang W, Wu G, Kelly KA, Meininger CJ. Tetrahydrobiopterin levels regulate endothelial cell proliferation. Am J Physiol Heart Circ Physiol Aug;281(2):H PMID: (5) Modulation of endothelial tetrahydrobiopterin levels. We previously demonstrated that increasing the tetrahydrobiopterin levels in endothelial cells by adenoviral delivery of the GTP cyclohydrolase gene would normalize blood vessel function in diabetes. We are currently developing tetrahydrobiopterin-loaded solid lipid nanoparticles that are taken orally and are selectively absorbed via the gastrointestinal lymphatics to deliver tetrahydrobiopterin to blood vessels oxidatively damaged by diabetes in order to reduce the vascular complications that contribute to morbidity and mortality of diabetes mellitus. Upregulation of tetrahydrobiopterin levels in oxidatively damaged endothelial cells not only reverses dysfunction caused by diabetes but also protects endothelial cells from future damage/dysfunction by increasing their endogenous pool of antioxidants. This novel therapeutic strategy has obvious advantages in terms of patient compliance for treatment of this and other chronic diseases associated with endothelial cell dysfunction. a) Meininger CJ, Cai S, Parker JL, Channon KM, Kelly KA, Becker EJ, Wood MK, Wade LA, Wu G. GTP cyclohydrolase I gene transfer reverses tetrahydrobiopterin deficiency and increases nitric oxide synthesis in endothelial cells and isolated vessels from diabetic rats. FASEB J Dec;18(15): doi: /fj fje. PMID: b) Hoang HH, Padgham SV, Meininger CJ. L-arginine, tetrahydrobiopterin, nitric oxide and diabetes. Curr Opin Clin Nutr Metab Care Jan;16(1): doi: /MCO.0b013e32835ad1ef. Review. PMID: Complete List of Peer-Reviewed Publications in MyBibliography: cending D. Research Support Ongoing Research Support: RU24DK McIndoe, R (PI); Meininger (Subcontract PI) 10/01/15-09/30/17 National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases BH4-Loaded Nanoparticles for Diabetes-Associated Cardiovascular Disease The overall goal of this research is to develop an effective therapeutic regimen for delivery of tetrahydrobiopterin (BH4) to endothelial cells exhibiting impaired function in order to modulate their ability to

5 synthesize nitric oxide, thereby improving vascular homeostasis and reducing the risk for subsequent vascular complications. Completed Research Support: R56DK A1 Gashev, A (PI). Meininger (Co-I) 09/15/14-08/31/16 National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases Bidirectional Regulatory Interactions Between Lymph Vessel and Adjacent Tissues The overall goal of this research was to investigate the regulatory mechanisms of interactions between mesenteric lymphatic vessels and mast cells in healthy states and during intestinal inflammation. Clinical Trial (Wu, G. and McNeal, C, Co-PIs); Meininger (Co-I) 04/01/13 10/31/16 International Council on Amino Acid Science Safety of Dietary Arginine Supplementation to Health Humans Specific Aim: The goal of this clinical trial was to determine the Observed Safe Level for oral administration of arginine in healthy humans. 11GRNT Meininger (PI) 07/01/11 06/30/13 American Heart Association, SouthCentral Affiliate Lymphatic Delivery of Tetrahydrobiopterin-Loaded Nanoparticles for Vascular Dysfunction in Diabetes The overall goal of this research was to optimize increases in tetrahydrobiopterin (BH4) and nitric oxide (NO) bioavailability in diabetic rat endothelial cells and isolated vessel segments using BH4-loaded solid lipid nanoparticles (SLNs), while validating the concept of orally delivered BH4-loaded SLNs to attenuate endothelial cell dysfunction in rat models of human diabetes. 10GRNT Wu (PI) Meininger (Co-I) 07/01/10-06/30/13 American Heart Association, SouthCentral Affiliate Leucine and Vascular Insulin Resistance in Diet-induced Obese Rats Specific aims: (1) Elucidate the role of leucine in vascular insulin resistance; and (2) Demonstrate a beneficial effect of dietary α-ketoglutarate supplementation in ameliorating vascular insulin resistance. R21-HL Meininger (PI) 07/01/09-06/30/12 National Institutes of Health Treating Endothelial Dysfunction with Targeted Nanoparticle-based BH4 Delivery Specific Aims: (1) Demonstrate modulation of tetrahydrobiopterin (BH4) and nitric oxide bioavailability in cultured diabetic rat endothelial cells, isolated vessel segments, and blood vessels in vivo by biodegradable nanoparticle-mediated BH4 delivery and (2) Validate the concept of targeted BH4 delivery to specific endothelial cells by utilizing LOX-1 antibody-conjugated nanoparticles to bind specific cell/vessel targets. R01-HL Eichler (PI); Meininger (Co-I) 09/01/09-08/31/11 National Institutes of Health Regulation of the Endothelial Citrulline-Nitric Oxide Cycle The overall goal of this research is to investigate the mechanisms by which physiologic and pathologic stimuli affect vascular function by regulating arginosuccinate synthase (AS). The aims of this proposal are to (1) explore the mechanisms of insulin-mediated regulation of AS, (2) examine the mechanism by which arginosuccinate synthase regulatory protein represses the synthesis of AS, and (3) examine the mechanisms underlying the actions of insulin on AS production in an animal model of diabetes.