Osmania University, Hyderabad, India, M.S. Genetics,
Jawaharlal Nehru University, New Delhi, India, M.Phil. Life Sciences,
Jawaharlal Nehru University, New Delhi, India, Ph.D. Life Sciences
University of California, San Diego, CA, Post-doctoral Fellowship
- Hemostasis and Thrombosis
- Membrane trafficking
- Cell signaling
- Cellular dynamics that regulate TF activity at cell surfaces and molecular mechanisms responsible for TF decryption.
- Establishing the pathophysiological significance of factor VIIa interaction with endothelial cell protein C receptor.
- Mechanisms by which tissue factor and EPCR contribute or influence pathogenesis of various diseases, including cancer and inflammation.
Tissue factor (TF)-dependent blood coagulation plays a primary role in hemostasis after tissue injury and also in pathogenesis of many thrombotic events, including atherosclerosis, acute coronary syndrome, septicemia, and cancer. Tissue factor functions as the cellular receptor for plasma clotting factor VII(a) and the formation of TF/VII(a) complexes on cell surfaces triggers the coagulation cascade. The proper regulation of TF expression is critical not only for maintenance of the hemostatic balance but also health in general. Despite extensive information available on the protein biochemistry of TF and its interaction with FVIIa, how TF functional expression is regulated on cell surfaces remains poorly understood. Most TF on surfaces of resting cells exist in an encrypted state with very little procoagulant activity, and TF has to undergo decryption to become fully active. The cellular microenvironment on the plasma membrane that controls TF activity and cellular mechanisms that are responsible for TF decryption are poorly defined.
The endothelial cell lining constitutes the interface between vascular tissue and circulating blood. In their quiescent state, endothelial cells provide a non-thrombogenic surface and express proteins that participate in anticoagulant mechanisms, such as endothelial cell protein C receptor (EPCR), thrombomodulin (TM), tissue factor pathway inhibitor-1, and are devoid of procoagulant TF. Being at the interface between blood and the vessel wall, the endothelial cells are positioned optimally to interact with circulating clotting factors. Until recently, it is believed that FVII/FVIIa does not interact with the endothelium as native endothelial cells do not express TF, the only known cofactor/receptor for FVII/FVIIa. Our recent studies have established that FVII/FVIIa bind to EPCR in a true-ligand fashion. The physiological significance and importance of FVIIa interaction with EPCR are yet to be explored.
Both TF and EPCR, whose primary function is to regulate clotting, also affect various pathophysiological processes, ranging from embryo development to cancer. Studies from our laboratory and others have shown that FVIIa bound to either TF or EPCR induces protease-activated receptors (PAR)-mediated cell signaling. Understanding of FVIIa-TF and FVIIa-EPCR-induced cell signaling pathways and the resultant cellular alterations would help in understanding how the receptors and proteases involved in clotting process can influence pathogenesis of various diseases.
Kothari H, Keshava S, Vatsyayan R, Mackman N, Rao LVM, Pendurthi UR. Role of tissue factor in Mycobacterium tuberculosis-induced inflammation and disease pathogenesis. Plos One 9: e114141, 2014.
Jeffers A, Owens S, Koenig K, Quaid B, Pendurthi UR, Rao LVM, Idell S, Tucker TA. Thrombin down-regulates tissue factor pathway inhibitor expression in PI3K/NFkB-depdent manner in human pleural mesothelial cells. Am J Res Cell Mol Biol. 2014, accepted.
Sundaram J, Pendurthi UR, smon CT, Rao LVM. Blockade of endothelial cell protein C receptor augments factor VIIa hemostatic effect in hemophilia treatment. Blood 124: 3031-3013, 2014.
Rao LVM Secretory group V phospholipase A2: a new player in thrombosis? J Thromb Haemost 12: 1918-1920, 2014.
Rao LVM, Esmon CT, Pendurthi UR. Endothelial cell C protein receptor: A multi-liganded and multi-functional receptor. Blood 124: 1553-1562, 2014.
Vatsyayan R, Kothari H, Macman N, Pendurthi UR, Rao LVM. Inactivation of factor VIIa by antithrombin in vitro, ex vivo and in vivo: Role of tissue factor and endothelial cell protein C receptor. Plos One 9: e103505, 2014.
Sundaram J, Keshava S, Esmon CT, Pendurthi UR, Rao LVM. Factor VIIa binding to endothelial cell protein C receptor protects vascular barrier integrity in vivo. J Thromb Haemost 12: 690-670, 2014.
Tucker TA, Jeffers A, Alvarez A, Owens S, Koenig K, Quaid B, Komissarov A, Florova G, Kothari H, Pendurthi UR, Rao LVM, Idell S. Plasminogen activator inhibitor-1 deficiency augments visceral mesothelial organization, intrapleural coagulation and lung restriction in mice with carbon black/bleomycin-Induced pleural injury. Am J Res Cell Mol Biol 50: 316-327, 2014.
Kothari H, Pendurthi UR, Rao LVM. Tissue factor purified from different cellular sources and non-deglycosylated tissue factor exhibit similar procoagulant activity. J Thromb Haemost 11: 2066-2068, 2013.
Keshava S, Kothari H, Rao LVM, Pendurthi UR. Influence of endothelial cell protein C receptor on breast cancer development. J Thromb Haemost 11: 2062-2065, 2013.
Kothari H, Pendurthi UR, Rao LVM. Analysis of tissue factor expression in various cell model systems: cryptic vs. active. J Thromb Haemost 11: 1353-1363, 2013.
Vatsyayan R, Kothari H, Pendurthi UR, Rao LVM. 4-Hydroxy-2-nonenal Enhances tissue actor activity in human monocytic cells via p38 MAPK activation-dependent phosphatidylserine exposure. Arterioscler Thromb Vasc Biol 33: 1601-1611, 2013.
Keshava S, Sahoo S, Tucker TT, Idell S, Rao LVM, Pendurthi UR. Endothelial Cell Protein C Receptor Opposes Mesothelioma Growth Driven by Tissue Factor. Cancer Research 73: 3963-3973, 2013.
Nayak RC, Keshava S, Esmon CT, Pendurthi UR, Rao LVM. Rab GTPases Regulate Endothelial Cell Protein C Receptor-mediated endocytosis and trafficking of factor VIIa. PLOS ONE 8: e59304, 2013.
Rao LVM, Pendurthi UR. Regulation of tissue factor coagulant activity on cell surfaces. J Thromb Haemost 10: 2242-2253, 2012.
Clark CA, Vatsyanan, Hedner U , Esmon CT, Pendurthi UR, Rao LVM. Endothelial cell protein C receptor-mediated redistribution and tissue-level accumulation of factor VIIa. J Thromb Haemost 10: 2383-2391, 2012.
Kothari HK, Rao LVM, Vankayalapati R, Pendurthi UR. Mycobacterium tuberculosis infection and tissue factor expression in macrophages. PlosOne 7: e45700, 2012.
Feinstein DI, Osterud B, Rao LVM. Samuel I. Rapaport, creator of the partial thromboplastin time and other landmark blood coagulation discoveries. J Thromb Haemost 10: 1719-1721, 2012.
Rao LVM, Kothari H, Pendurthi UR. Tissue factor encryption and decryption: Facts and controversies. Thromb Res 129 (suppl 2): 513-517, 2012.
Gopalakrishnan R, Pendurthi UR, Hedner U, Agerso H, Esmon CT, Rao LVM. Influence of endothelial cell protein C receptor on plasma clearance of factor VIIa. J Thromb Haemost 10: 971-973, 2012.
Sen P, Clark CA, Gopalakrishnan R, Hedner U, Esmon CT, Pendurthi UR, Rao LVM. Factor VIIa binding to endothelial cell protein C receptor: Differences between mouse and human systems. Thromb Haemost 107: 951-96, 2012 (cover photo).
Rao LVM, Kothari H, Pendurthi UR. Tissue factor: Mechanisms of decryption. Frontiers in Bioscience E4: 1513-1527, 2012.
Tucker TA, Williams L, Koenig K, Kothari H, Komissarov A, Florova G, Mazar AP, Allen TC, Rao LVM, Idell S. Lipoprotein receptor-related protein 1 regulates collagen 1 expression, proteolysis, and migration in human pleural mesothelial cells. Am J Res Cell Mol Biol 46:196-206, 2012.
Williams L Tucker TA, Koenig K, Allen T, Rao LVM, Pendurthi UR, Idell SI. Tissue factor pathway inhibitor attenuates the progression of malignant pleural mesothelioma in nude mice. Am J Res Cell Mol Biol 46: 173-209, 2012.