Srinivasan, Sathish

My 101

The heart pumps blood, which carries oxygen and other nutrients throughout the body. Plasma is released from blood vessels to nourish the tissues. The lymphatic system functions to return this tissue fluid to blood circulation. A condition called lymphedema results when the lymphatic vasculature is damaged. Accumulating fluids cause swelling in the tissues that can lead to infections, inflammation and pain. Surgical damage to lymphatic vessels causes lymphedema in millions of people every year. Currently, only conservative treatments like massage and compression bandages are available. In my lab, we are studying the genes and signaling pathways responsible for the development and growth of the lymphatic vasculature.

We also focus on the role of the valves that regulate fluid flow within the vascular system. Valves are present within lymphatic vessels, veins and in the heart. A range of diseases such as spider veins, varicose veins, lymphedema and cardiac valve defects occur if the valves are not formed correctly or if they are damaged by injury or disease. By studying the genes responsible for the formation or functioning of valves, we can develop better strategies to repair these problems.

Research

My goals are to understand the molecular mechanisms regulating lymphatic and valvular endothelial cell development and maintenance.

The mammalian lymphatic vasculature is important for returning the extravasated plasma fluids in tissue space back to blood circulation, absorption of digested lipids from the intestine and in immune surveillance. Lymphedema is a disfiguring and mobility restricting disease that results due to the abnormal functioning of the lymphatic vasculature. Lymphedema is a common disorder that results either due to mutations in genes that regulate lymphatic vascular development or more often due to infection or surgical damage to the lymphatic vessels. Lymphatic vasculature is also considered as a major route for tumor metastasis especially melanoma and breast cancer. Despite its importance, diagnosis of lymphatic disorders and the identification of new targets to treat those ailments are limited.

Valves regulate the unidirectional flow of fluids (blood or lymph) in the mammalian vascular system. Valves are present in the heart, veins and the lymphatic vessels and are crucial for the normal physiology of the cardiovascular system. In addition, there is also a unique type of valve known as the lymphovenous valve that regulates the return of lymph fluid including all of the digested lipids (approximately 2 liters per day in an average human being) back to venous circulation.

Congenital cardiac valve defects are common causes for childhood mortality and morbidity. Calcification of cardiac valves occurs in approximately 10% of people who are at least 65 years old. This leads to valvular stenosis that could result in atherosclerosis, pulmonary edema, thromboembolism, cardiac hypertrophy and sudden cardiac death. A high-fat diet is known to aggravate this disease. Infection and non-infection (cancer) related endocarditis also damages cardiac valves.

In the aging population a range of venous valve defects such as spider veins, varicose veins and venous insufficiency are common. Incompetent venous valves results in ineffective blood flow causing pooling of blood and thrombosis. This result in embolism, problems in wound healing and tissue necrosis. In severe cases this leads to the stroke or amputation of the limbs.

Defects in formation or functioning of lymphatic valves cause lymphedema. Lymphectomy performed during breast cancer treatment frequently damages both lymphatic vessels and valves resulting in lymphedema.

No information is currently available regarding lymphovenous valves in human disease although using mouse models, we have recently demonstrated that defects in these valves could lead to lymphedema and chylothorax (Geng, et al 2016). We believe that similar to the other cardiovascular valves they are likely to undergo aging related degeneration.

Despite their importance our understanding of valves during normal development and in disease is limited. With increase in the median age of the general population and with improving treatment options for cancer we have an urgent need to better understand the biology of valves and develop treatment methodologies to treat valve disorders beyond conventional synthetic replacement valves that are associated with significant mortality and morbidity.

Despite their differences, the development of both lymphatic and valvular endothelial cells is regulated by a common set of transcription factors and signaling molecules. Our goal is to understand these molecular mechanisms and translate this knowledge into effective treatments.

Brief CV

Education
B.Tech., Anna University, Chennai, India, 1999
Ph.D., Tulane University Medical Center, New Orleans, LA, 2003

Honors and Awards
2003 Morris F. Shaffer and Margret H.D. Smith-Shaffer Award for Excellence in Research, Tulane University, New Orleans, LA
2003 Keystone Symposia Scholarship, Keystone Symposium on Molecular Targets for Cancer Therapy, Banff, Canada
2005 Award for Best Scientific Talk, Vanderbilt University retreat on developmental biology, Paris Landing State Park, TN
2006 Outstanding Poster Award, Developmental vascular biology workshop II, North American Vascular Biology Organization (NAVBO), Asilomar, CA
2008 Travel Award, Developmental vascular biology workshop III, North American Vascular Biology Organization (NAVBO), Asilomar, CA
2010 Travel Award, Developmental vascular biology workshop IV, North American Vascular Biology Organization (NAVBO), Asilomar, CA
2017 Fred Jones Award for Scientific Achievement

Membership
North American Vascular Biology Organization
Society for Developmental Biology
American Heart Association

Joined OMRF Scientific Staff in 2013

Publications

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Recent Publications

Mahamud MR, Geng X, Ho YC, Cha B, Kim Y, Ma J, Chen L, Myers G, Camper S, Mustacich D, Witte M, Choi D, Hong YK, Chen H, Varshney G, Engel JD, Wang S, Kim TH, Lim KC, Srinivasan RS. GATA2 controls lymphatic endothelial cell junctional integrity and lymphovenous valve morphogenesis through miR-126. Development, 2019 October, PMID: 31582413, PMCID: PMC6857586

Yang Y, Cha B, Motawe ZY, Srinivasan RS, Scallan JP. VE-Cadherin Is Required for Lymphatic Valve Formation and Maintenance. Cell Rep 28:2397-2412.e4, 2019 August, PMID: 31461654, PMCID: PMC6743082

Cha B, Geng X, Mahamud MR, Zhang JY, Chen L, Kim W, Jho EH, Kim Y, Choi D, Dixon JB, Chen H, Hong YK, Olson L, Kim TH, Merrill BJ, Davis MJ, Srinivasan RS. Complementary Wnt Sources Regulate Lymphatic Vascular Development via PROX1-Dependent Wnt/β-Catenin Signaling. Cell Rep 25:571-584.e5, 2018 October, PMID: 30332639, PMCID: PMC6264919

Selected Publications

Crosswhite PL, Podsiadlowska JJ, Curtis CD, Gao S, Xia L, Srinivasan RS, Griffin CT. CHD4-regulated plasmin activation impacts lymphovenous hemostasis and hepatic vascular integrity. J Clin Invest. 2016 Jun 1;126(6):2254-66. PMID: 27140400 PMCID: PMC4887170

Liu X, Pasula S, Song H, Tessneer KL, Dong Y, Hahn S, Yago T, Brophy ML, Chang B, Cai X, Wu H, McManus J, Ichise H, Georgescu C, Wren JD, Griffin C, Xia L, Srinivasan RS, Chen H. Temporal and spatial regulation of epsin abundance and VEGFR3 signaling are required for lymphatic valve formation and function. Sci Signal. 2014 Oct 14;7(347):ra97. PMID: 25314967 PMCID: PMC4226761

Srinivasan RS, Escobedo N, Yang Y, Interiano A, Dillard ME, Finkelstein D, Mukatira S, Gil HJ, Nurmi H, Alitalo K, Oliver G. The Prox1-Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors. Genes Dev. 2014 Oct 1;28(19):2175-87. PMID: 25274728 PMCID: PMC4180978

Srinivasan RS, Oliver G. Prox1 dosage controls the number of lymphatic endothelial cell progenitors and the formation of the lymphovenous valves. Genes Dev. 2011 Oct 15;25(20):2187-97. PMCID: PMC3205588

Srinivasan RS, Geng X, Yang Y, Wang Y, Mukatira S, Studer M, Porto MP, Lagutin O, Oliver G. The nuclear hormone receptor Coup-TFII is required for the initiation and early maintenance of Prox1 expression in lymphatic endothelial cells. Genes Dev. 2010 Apr 1;24(7):696-707. PMID: 22012621 PMCID: PMC3205588

Srinivasan RS, Dillard ME, Lagutin OV, Lin FJ, Tsai S, Tsai MJ, Samokhvalov IM, Oliver G. Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature. Genes Dev. 2007 Oct 1;21(19):2422-32. PMID: 17908929 PMCID: PMC1993873