Rao, L. Vijaya Mohan, Ph.D.
Professor - Department of Cellular and Molecular Biology
M.S. , Genetics, Osmania University, Hyderabad, India
M.Phil., Life Sciences, Jawaharlal Nehru University, New Delhi, India
Ph.D., Life Sciences, Jawaharlal Nehru University, New Delhi, India
Post-doctoral Fellowship, University of California, San Diego, CA
Hemostasis and Thrombosis, Membrane trafficking, Cell signaling
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.
We are currently focusing on the following questions
- 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.
National Institute of Health, American Heart Association, Novo Nordisk
Selected Papers and Abstracts:
- 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.F
- 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.
- Sen P, Nayak R, Clark C, Gopalakrishnan R, Esmon CT, Pendurthi UR, Rao LVM. Factor X binding to endothelial cell protein C receptor: A comparison with factor VIIa and activated protein C. Blood 118: 2635-2636, 2011.
- Kothari H, Rao LVM, Pendurthi UR. Glycosylation of tissue factor is not essential for its transport or functions. J Thromb Haemost 9: 1511-1520, 2011. (Commentary by J Morrissey, Low-carb tissue factor, J Thromb Haemost 9: 1508-1510, 2011).
- Sen P. Gopalakrishnan R, Kothari H, Clark C, Keshava S, Esmon CT, Pendurthi UR, Rao LVM. Factor VIIa bound to endothelial cell protein C receptor activates protease activated receptor-1 and mediates cell signaling and barrier protection. Blood 117, 3199-3208, 2011.
- Sen P, Komissarov AA, Florova G, Idell S, Pendurthi UR, Rao LVM. Plasminogen activator inhibitor-1 inhibits factor VIIa bound to tissue factor. J Thromb Haemost 9, 531-539, 2011.
- Dhiman R, Bandaru A, Saha S, Barnes PF, Tvinnereim A, Nayak RC, Paidipally P, Valluri V, Rao LVM, Vankayalapati R. c-Maf-dependent growth of Mycobacterium tuberculosis in a CD14(hi) subpopulation of monocyte-derived macrophages. J. Immunol 186, 1638-1645, 2011.
- Gopalakrishnan R, Hedner U, Ghosh S, Nayak R, Allen T, Pendurthi UR, Rao LVM. Bio-distribution of pharmacologically administered rFVIIa. J Thromb Haemost 8, 301-310, 2010.
- Rao LVM, Mackman N. Factor VIIa and tissue factor- from cell biology to animal models. Thromb Res 125, S1-S3, 2010.
- Pendurthi UR, Rao LVM. Factor VIIa interaction with endothelial cells and endothelial cell protein C receptor. Thromb Res 125, S19-S22, 2010.
- Sen P, Ghosh S, Ezban M, Pendurthi UR, Rao LVM. Effect of glycoPEGylation on factor VIIa binding and internalization. Haemophilia 16, 338-348, 2010.
- Sen P, Neuenschwander P, Pendurthi UR, Rao LVM. Analysis of factor VIIa binding to relipidated tissue factor using surface plasmon resonance. Blood coagulation and fibrinolysis 21, 376-379, 2010.
- Kothari H, Nayak K, Rao LVM, Pendurthi UR. Cystine186-cystine209 disulfide bond is not essential for the procoagulant activity of tissue factor or for its de-encryption. Blood 115, 427304283, 2010.
- Sen P, Sahoo S, Pendurthi UR, Rao LVM. Zinc modulates the interaction of protein C and activated protein C with endothelial cell protein C receptor. J Biol Chem 285, 20410-20420, 2010.
- Han D-Y, Nie H-G, Gu X, Nayak R, Su X-E, Fu J, Chang Y, Rao LVM, Ji H-L. K+ channel openers restore verapamil-inhibited lung fluid resolution and transepithelial ion transport. Respiratory Res 11, 65, 2010.
- Gopalakrishnan R, Hedner U, Clark C, Pendurthi UR, Rao LVM. rFVIIa transported from blood stream into tissues is functionally active. J Thromb Haemost 8, 2318-2321, 2010.