Nihar Ranjan Nayak (ft5330)

Research in our laboratory is focused on understanding the mechanisms of vascular development and remodeling during implantation and pregnancy, with particular emphasis on understanding the pathophysiology of pregnancy-related vascular complications. We believe that most of the pregnancy-related vascular complications manifested late in gestation, including preeclampsia, have their origins early in pregnancy. Thus, the main goal of our research is to identify the abnormalities in implantation that may contribute to the development of various diseases of pregnancy. We use human tissue samples and both animal and culture models to address our various research questions.

The significance of pathogenetic processes reported in various pregnancy disorders, including preeclampsia, has largely been speculative, primarily due to the absence of experimental models for tissue-specific manipulation of gene functions at the maternal-fetal interface. Thus, one of our major goals is to develop methods for tissue-specific gene manipulation in the mouse placenta and decidua. A related goal is to develop methods for the delivery of various candidate molecules specifically to these tissues for therapeutic purposes. Most notably, our recently developed lentivirus-mediated placenta- and decidua-specific gene expressions systems and method of repetitively tracking gene expression in these tissues throughout pregnancy by live bioluminescence imaging have provided invaluable tools for studying the functions and interactions of candidate molecules at the maternal-fetal interface. We have also accomplished another key milestone in the creation of Tet3G transgenic mice for highly sensitive doxyclycline-indudible gene expression and demonstrated their effectiveness for tissue-specific on-off control of gene expression throughout pregnancy. Now we have the ability to test specific hypotheses about candidate molecules at the maternal-fetal interface at specific windows of time during pregnancy, overcoming one of the major technical hurdles in the field of pregnancy research and allowing us to address fundamental questions about the etiologies of several pregnancy disorders.

Indeed, by taking advantage of these unique tools, we made a field-changing discovery – that vascular endothelial growth factor (VEGF) of maternal origin can stimulate soluble fms-like tyrosine kinase (sFlt1) production by the placenta and that this signaling is involved in the etiology of the serious pregnancy disorder preeclampsia. Furthermore, by placenta-specific knockdown of sFlt1, we also demonstrated for the first time that sFlt1 plays an essential role in maintaining placental vascular integrity and that overexpression of sFlt1 in preeclampsia may, in fact, serve a critical protective function for the placenta and fetus through its sequestration of excess maternal VEGF. These findings not only offer a novel model for the etiology of preeclampsia and insights for development of new therapeutic strategies for its treatment, but also define a previously unappreciated role for placental sFlt1 during pregnancy.

We are currently performing several multidisciplinary collaborative studies with investigators both from academia and industry. Our work has been funded by a number of institutions/agencies, including the NIH, March of Dimes, ACOG, Lalor Foundation, Mellon Foundation and Preeclampsia Foundation, and we have published in numerous prestigious journals, including the Journal of Clinical Investigation, FASEB Journal, PloS ONE, PNAS, Nature Medicine, Journal of Clinical Endocrinology and Metabolism, Endocrinology and Biology of Reproduction.

• Fan X, Rai A, Kambham N, Sung J, Singh N, Petitt M, Dhal S, Sutton RE, Druzin ML, Gambhir SS, Ambati BK, Cross JC and Nayak NR. Endometrial VEGF induces placental sFlt1 leading to pregnancy complications. Journal of Clinical Investigation, 2014, In press.
• Fan X, Petitt M, Gamboa M, Huang M, Dhal S, Druzin ML, Wu JC, Chen-Tsai Y, Nayak NR. Transient, inducible, placenta-specific gene expression in mice. Endocrinology. 2012 Nov;153(11):5637-44.
• Fan X, Ren P, Dhal S, Bejerano G, Goodman SB, Druzin ML, Gambhir SS, Nayak NR. Noninvasive monitoring of placenta-specific transgene expression by bioluminescence imaging. PLoS One. 2011 Jan 21;6(1):e16348.
• Sung JF, Fan X, Dhal S, Dwyer BK, Jafari A, El-Sayed YY, Druzin ML, Nayak NR. Decreased circulating soluble Tie2 levels in preeclampsia may result from inhibition of vascular endothelial growth factor (VEGF) signaling. J Clin Endocrinol Metab. 2011 Jul;96(7):E1148-52.
• Fan X, Krieg S, Kuo CJ, Wiegand SJ, Rabinovitch M, Druzin ML, Brenner RM, Giudice LC, Nayak NR. VEGF blockade inhibits angiogenesis and reepithelialization of endometrium. FASEB J. 2008 Oct;22(10):3571-80.

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