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.
Recent and Selected Publications List
Ansari SA, Pendurthi UR, Rao LVM. The lipid peroxidation product 4-hydroxy-2-nonenal induces tissue factor decryption via ROS generation and the thioredoxin system.Blood Adv. 2017 Nov 27;1(25):2399-2413. doi: 10.1182/bloodadvances.2017010132. eCollection 2017 Nov 28. PubMed PMID: 29296890; PubMed Central PMCID: PMC5729625.
Keshava S, Sundaram J, Rajulapati A, Esmon C, Pendurthi U, Rao LVM. Factor VIIa interaction with EPCR modulates the hemostatic effect of rFVIIa in hemophilia therapy: Mode of its action.Blood Adv. 2017 Jun 27;1(15):1206-1214. doi: 10.1182/bloodadvances.2016004143. PubMed PMID: 28932824; PubMed Central PMCID: PMC5602564.
Wang J, Pendurthi UR, Rao LVM. Sphingomyelin encrypts tissue factor: ATP-induced activation of A-SMase leads to tissue factor decryption and microvesicle shedding.Blood Adv. 2017 May 23;1(13):849-862. doi: 10.1182/bloodadvances.2016003947. PubMed PMID: 28758160; PubMed Central PMCID: PMC5531194.
Keshava S, Rao LV, Pendurthi UR. Intrapleural Adenoviral-mediated Endothelial Cell Protein C Receptor Gene Transfer Suppresses the Progression of Malignant Pleural Mesothelioma in a Mouse Model.Sci Rep. 2016 Nov 11;6:36829. doi: 10.1038/srep36829. PubMed PMID: 27833109; PubMed Central PMCID: PMC5104979.
Keshava S, Sundaram J, Rajulapati A, Pendurthi UR, Rao LV. Pharmacological concentrations of recombinant factor VIIa restore hemostasis independent of tissue factor in antibody-induced hemophilia mice.J Thromb Haemost. 2016 Mar;14(3):546-50. doi: 10.1111/jth.13244. Epub 2016 Feb 15. PubMed PMID: 26727350; PubMed Central PMCID: PMC4785069.
Ansari SA, Pendurthi UR, Sen P, Rao LV. The Role of Putative Phosphatidylserine-Interactive Residues of Tissue Factor on Its Coagulant Activity at the Cell Surface.PLoS One. 2016 Jun 27;11(6):e0158377. doi: 10.1371/journal.pone.0158377. eCollection 2016. PubMed PMID: 27348126; PubMed Central PMCID: PMC4922585.
Jeffers A, Owens S, Koenig K, Quaid B, Pendurthi UR, Rao VM, Idell S, Tucker TA. Thrombin down-regulates tissue factor pathway inhibitor expression in a PI3K/nuclear factor-κB-dependent manner in human pleural mesothelial cells.Am J Respir Cell Mol Biol. 2015 Jun;52(6):674-82. doi: 10.1165/rcmb.2014-0084OC. PubMed PMID: 25303460; PubMed Central PMCID: PMC4491127.
Sundaram J, Pendurthi UR, Esmon CT, Rao LV. Blockade of endothelial cell protein C receptor augments factor VIIa hemostatic effect in hemophilia treatment.Blood. 2014 Nov 6;124(19):3031-3. doi: 10.1182/blood-2014-09-600254. PubMed PMID: 25377566; PubMed Central PMCID: PMC4467861.
Mohan Rao LV, Esmon CT, Pendurthi UR. Endothelial cell protein C receptor: a multiliganded and multifunctional receptor.Blood. 2014 Sep 4;124(10):1553-62. doi: 10.1182/blood-2014-05-578328. Epub 2014 Jul 21. Review. PubMed PMID: 25049281; PubMed Central PMCID: PMC4155268.
Sundaram J, Keshava S, Gopalakrishnan R, Esmon CT, Pendurthi UR, Rao LV. Factor VIIa binding to endothelial cell protein C receptor protects vascular barrier integrity in vivo.J Thromb Haemost. 2014 May;12(5):690-700. PubMed PMID: 24977291; PubMed Central PMCID: PMC4085578.
Tucker TA, Jeffers A, Alvarez A, Owens S, Koenig K, Quaid B, Komissarov AA, Florova G, Kothari H, Pendurthi U, Mohan Rao LV, 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 Respir Cell Mol Biol. 2014 Feb;50(2):316-27. doi: 10.1165/rcmb.2013-0300OC. PubMed PMID: 24024554; PubMed Central PMCID: PMC3930954.
Kothari H, Keshava S, Vatsyayan R, Mackman N, Rao LV, Pendurthi UR. Role of tissue factor in Mycobacterium tuberculosis-induced inflammation and disease pathogenesis.PLoS One. 2014 Dec 2;9(12):e114141. doi: 10.1371/journal.pone.0114141. eCollection 2014. PubMed PMID: 25462128; PubMed Central PMCID: PMC4252100.
Vatsyayan R, Kothari H, Mackman N, Pendurthi UR, Rao LV. 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. 2014 Aug 7;9(8):e103505. doi: 10.1371/journal.pone.0103505. eCollection 2014. PubMed PMID: 25102166; PubMed Central PMCID: PMC4125150.
Keshava S, Sahoo S, Tucker TA, Idell S, Rao LV, Pendurthi UR. Endothelial cell protein C receptor opposes mesothelioma growth driven by tissue factor.Cancer Res. 2013 Jul 1;73(13):3963-73. doi: 10.1158/0008-5472.CAN-12-1690. Epub 2013 Mar 28. PubMed PMID: 23539451; PubMed Central PMCID: PMC3702650.
Sen P, Nayak R, Clark CA, Gopalakrishnan R, Esmon CT, Pendurthi UR, Rao LV. Factor X binding to endothelial cell protein C receptor: comparison with factor VIIa and activated protein C. 2011 Sep 1;118(9):2635-6. doi: 10.1182/blood-2011-05-354571. PubMed PMID: 21885613; PubMed Central PMCID: PMC3363977.
Nayak RC, Sen P, Ghosh S, Gopalakrishnan R, Esmon CT, Pendurthi UR, Rao LV. Endothelial cell protein C receptor cellular localization and trafficking: potential functional implications. 2009 Aug 27;114(9):1974-86. doi: 10.1182/blood-2009-03-208900. Epub 2009 Jul 8. PubMed PMID: 19587380; PubMed Central PMCID: PMC2738580.
Pendurthi UR, Ghosh S, Mandal SK, Rao LV. Tissue factor activation: is disulfide bond switching a regulatory mechanism? 2007 Dec 1;110(12):3900-8. Epub 2007 Aug 28. PubMed PMID: 17726162; PubMed Central PMCID: PMC2190609.
Ghosh S, Pendurthi UR, Steinoe A, Esmon CT, Rao LV. Endothelial cell protein C receptor acts as a cellular receptor for factor VIIa on endothelium.J Biol Chem. 2007 Apr 20;282(16):11849-57. Epub 2007 Feb 27. PubMed PMID: 17327234; PubMed Central PMCID: PMC2591933.
Hjortoe GM, Petersen LC, Albrektsen T, Sorensen BB, Norby PL, Mandal SK, Pendurthi UR, Rao LV. Tissue factor-factor VIIa-specific up-regulation of IL-8 expression in MDA-MB-231 cells is mediated by PAR-2 and results in increased cell migration. 2004 Apr 15;103(8):3029-37. Epub 2004 Jan 8. PubMed PMID: 15070680; PubMed Central PMCID: PMC2837482.
Pendurthi UR, Allen KE, Ezban M, Rao LV. Factor VIIa and thrombin induce the expression of Cyr61 and connective tissue growth factor, extracellular matrix signaling proteins that could act as possible downstream mediators in factor VIIa x tissue factor-induced signal transduction.J Biol Chem. 2000 May 12;275(19):14632-41. PubMed PMID: 10799550.
Rao LV, Williams T, Rapaport SI. Studies of the activation of factor VII bound to tissue factor. 1996 May 1;87(9):3738-48. PubMed PMID: 8611699.
Zivelin A, Rao LV, Rapaport SI. Mechanism of the anticoagulant effect of warfarin as evaluated in rabbits by selective depression of individual procoagulant vitamin K-dependent clotting factors.J Clin Invest. 1993 Nov;92(5):2131-40. PubMed PMID: 8227329; PubMed Central PMCID: PMC288391.
Le DT, Rapaport SI, Rao LV. Relations between factor VIIa binding and expression of factor VIIa/tissue factor catalytic activity on cell surfaces.J Biol Chem. 1992 Aug 5;267(22):15447-54. PubMed PMID: 1639786
Sandset PM, Warn-Cramer BJ, Rao LV, Maki SL, Rapaport SI. Depletion of extrinsic pathway inhibitor (EPI) sensitizes rabbits to disseminated intravascular coagulation induced with tissue factor: evidence supporting a physiologic role for EPI as a natural anticoagulant.Proc Natl Acad Sci U S A. 1991 Feb 1;88(3):708-12. PubMed PMID: 1899482; PubMed Central PMCID: PMC50882.
Fleck RA, Rao LV, Rapaport SI, Varki N. Localization of human tissue factor antigen by immunostaining with monospecific, polyclonal anti-human tissue factor antibody.Thromb Res. 1990 Jul 15;59(2):421-37. PubMed PMID: 2237820.
Rao LV, Rapaport SI. Factor VIIa-catalyzed activation of factor X independent of tissue factor: its possible significance for control of hemophilic bleeding by infused factor VIIa. 1990 Mar 1;75(5):1069-73. PubMed PMID: 2306514.
Rao LV, Rapaport SI. Activation of factor VII bound to tissue factor: a key early step in the tissue factor pathway of blood coagulation.Proc Natl Acad Sci U S A. 1988 Sep;85(18):6687-91. PubMed PMID: 3261869; PubMed Central PMCID: PMC282042.
Rao LV, Rapaport SI, Bajaj SP. Activation of human factor VII in the initiation of tissue factor-dependent coagulation. 1986 Sep;68(3):685-91. PubMed PMID: 3488776.
Membrane phospholipids: The key regulator of tissue factor encryption/decryption (PI)
Direct Costs: $1,000, 000
Period: 09-01-15 to 07-31-19
Source: National Heart, Lung, and Blood Institute
Development of Novel Bypass Therapies in Treating Hemophilia (PI)
Direct Costs: $204,220
Period: 12-01-15 to 11-30-17
FVIIa interaction with endothelial cell protein C receptor (PI)
Direct Costs: $1,020,000
Period: 09-01-16 to 08-31-2020
Source: National Heart, Lung, and Blood Institute
LR769 rFVIIa accumulation and retention in knee joints of wild-type and hemophilia mice (PI)
Direct Costs: $124,917
Period: 11-01-16 to 10-31-2018
Source: HEMA Biologics