Preeclampsia (PE) is the most common medical complication of pregnancy and affects 5-10% of pregnant women. It is the leading cause of maternal death in developing countries and premature delivery in developed nations. PE is characterized by new onset hypertension and proteinuria occurring after 20 weeks of gestation. Currently, the only treatment for PE is delivery. Recent research has shown that circulating anti-angiogenic proteins are associated with and may be involved in the pathogenesis of PE. In humans, antiangiogenic proteins (soluble fms-like tyrosine kinase-sFlt1 and soluble endoglin-sEng) are elevated, while levels of pro- angiogenic proteins (Placental Growth Factor-PlGF) are reduced in women prior to the clinical signs and symptoms of PE. Another observation which is supported by rapidly accumulating data is that exposure to this anti-angiogenic milieu during the pregnancy results in significant increase in cardiovascular mortality later in life. Mechanisms of this delayed "toxicity" are not clear. Long-term, renal function was shown to be impaired in significant proportion of women with past history of PE with "dose-response" like correlation observed: exposure to severe PE or recurrent PE, higher the chance of ESRD later in life. Some biologic evidence exists, that endothelial injury and possibly epigenetic changes in the vasculature is the starting point of those sequelae. Careful dissection of the pathophysiologic processes involved will help in identification of modifiable risk factors associated with the condition as well as recognition of suitable therapeutic targets with ultimate goal to reduce the sequelae. The applicant intends to do in vivo (on rodents) studies to investigate the prior preeclampsia in the pathogenesis of long term complications such as chronic renal failure. This work will not only advance the understanding of the role of angiogenic proteins in PE, but will also provide the necessary knowledge for development of drug therapies aimed at reducing sFlt1 and sEng toxicity in microvasculature of different organs later in life. Systemic vascular health and in particular glomerular endothelial "health" will be evaluated in setting of PE model alone or in addition to various know cardiovascular risk factors. Effort to identify potential mechanism will be made by means of analysis of inflammatory and endothelial function profiling in the proposed experimental groups. Pharmacologic interventions will be made aimed at elucidating relevant biological pathways involved, which ultimately could lead to identification of therapeutic targets. The proposed work will be performed in the laboratory of Dr. S. Ananth Karumanchi, an expert in PE biology, in the outstanding academic and research environment of Beth Israel Deaconess Medical Center and Harvard Medical School. The applicant is a Graduating Nephrology Fellow with rapidly developing and productive basic research background committed to research, understanding preeclampsia and reducing its impact on long term cardiovascular and renal morbidity and mortality. The combined expertise of mentors and collaborators will provide a unique opportunity for the applicant to achieve the goals of this project and to start a career as an independent investigator.
The proposed work will have immediate benefits as identification of the suitable therapeutic targets can lead to developing preventative strategy aimed at cardiovascular and renal protection of the women exposed to the PE, ultimately reducing burden of those conditions later in life. Currently, the treatment of PE ends with delivery of the fetus and no recommendations exist regarding the risk modification strategies or therapies needed postpartum. Clear identification of pathogenic pathways leading to endothelial injury perpetuation after prior exposure to PE is necessary for the development of novel preventative therapies.