Kirk P. Conrad, M.D.
Office: MSB MG-40A
Co-Organizer of the Reproductive and Perinatal Biology Research Program (http://www.perinatal.ufl.edu)
A long-standing research interest is to understand the mechanisms underlying the massive systemic maternal vasodilation and increased arterial compliance that transpire during normal pregnancy. Another is the dysregulation of these maternal circulatory adaptations in preeclampsia (a hypertensive disease of pregnancy), and the potential etiological role of aberrant endometrial maturation in the defective placentation associated with preeclampsia and other placental syndromes such as intrauterine growth restriction. Ultimately the goal is to apply the new knowledge gained from these investigations towards the development of mechanistic-based preventative, therapeutic and curative measures for these obstetrical diseases.
We found that the ovarian hormone relaxin is a potent vasodilator in the systemic and renal circulations, and that it contributes to the remarkable changes in the vasculature during pregnancy. These discoveries provided the scientific basis and motivation for pursuing the hormone as a therapy for afterload reduction and improvement of renal function in heart failure (ClinicalTrials.gov Identifier: NCT02064868), and they further suggested a therapeutic role in preeclampsia. We unveiled endothelial mechanisms of systemic vasodilation in pregnancy, and then our independent investigations of the cardiovascular effects of pregnancy and relaxin converged, leading to the elucidation of endothelial mechanisms for both “rapid” and “sustained” vasodilation by relaxin. We also observed that, unexpectedly, relaxin was equally potent in the vasculature of males, and to explain this finding we hypothesized the existence of local relaxin ligand-receptor expression and function in arteries, which we subsequently supported with both molecular and functional evidence. More recently, we found a new role for relaxin in bone marrow angiogenic progenitor cell mobilization and function, and in the context of pregnancy. A final aim has been to apply the “lessons learned from pregnancy” to further understand and treat cardiovascular disease in the non-pregnant population (e.g., heart failure).
We always strive to translate discoveries made in preclinical investigations to humans. As one example, we are currently investigating the cardiovascular adaptations and obstetrical outcomes of pregnancies in women conceiving by Assisted Reproductive Technologies (ART) (in comparison to spontaneously conceived pregnancies), because ART occurs in the setting of nil or as many as 20 corpora lutea, thus dramatically effecting the circulating levels of relaxin and other potentially vasoactive corpus luteal hormones. As another example, we recently investigated global gene expression in chorionic villus samples from women who later developed preeclampsia. After secondary analyses of the 356 genes altered in the CVS from women who developed preeclampsia, we find that as many as 154 genes are associated with decidualization or in this case, inadequate decidualization. Dr. Conrad and colleagues at the University of Florida are well situated to take these exciting findings to the next level. A long-term goal is to understand the etiology of preeclampsia, which will facilitate discovery of biomarkers for disease prediction, and strategies for prophylaxis and therapy. We believe that it is especially important to integrate Reproductive and Perinatal Medicine, in order to unveil etiology and develop preventative therapies for adverse pregnancy and neonatal outcomes.
Examples of Original Publications, Invited Reviews and Book Chapters:
Conrad KP. G-protein coupled receptors as potential drug candidates in preeclampsia: targeting the relaxin-insulin-like family peptide receptor 1 for treatment and prevention. Human Reproduction Update (Invited review). 2016 Jul 6. [Epub ahead of print].
Rabaglino MB, Post Uiterweer ED, Jeyabalan A, Hogge WA, and Conrad KP. A bioinformatics approach reveals evidence for impaired endometrial maturation before and during early pregnancy in women who developed preeclampsia. Hypertension 65:421-429, 2015.
Conrad KP, Stillman IE., and Lindheimer MD The Kidney in Normal Pregnancy and Preeclampsia. In: Chesley’s Hypertensive Disorders in Pregnancy: Fourth Edition. Robert N. Taylor, James M. Roberts, F. Gary Cunningham, and Marshall D. Lindheimer (eds.). 4th Edition; Elsevier Academic Press; Chapter 16 pps. 335-377; 2015.
Jelinic M., Leo C.H., Post Uiterweer E.D., Sandow S.L., Gooi J.H., Wlodek M.E., Conrad K.P., Parkington H., Tare M., and Parry L.J. Localization of relaxin receptors in arteries and veins, and region-specific increases in compliance and bradykinin-mediated relaxation after in vivo relaxin treatment. FASEB J. 28:275-87, 2014.
Conrad KP and Davison JM. The renal circulation in normal pregnancy and preeclampsia. Am J Physiol. Renal Fluid and Electrolyte Physiol. 306:F1121-35, 2014 (Invited Review).
Conrad K.P. and Baker V.L. Corpus luteal contribution to maternal pregnancy physiology and outcomes in assisted reproductive technologies. Am. J. Physiol. Regulatory Integrative Comp. Physiol. 304:R69-72, 2013 (Perspectives).
Conrad K.P. and Karumanchi S.A. Renal Physiology and Disease in Pregnancy. In: Seldin and Giebisch’s The Kidney. Physiology and Pathophysiology: Fifth Edition. R.J. Alpern, M.J. Caplan, O.W. Moe eds. Academic Press, San Diego. 2689-2761, 2013.
*Segal M.S., Sautina L., Li S., Diao Y., Agoulnik A.I., Kielczewski J, McGuane J.T., Grant M.B., and Conrad K.P. Relaxin increases human endothelial progenitor cell NO and migration and vasculogenesis in mice. Blood 119:629-36, 2012.
Vodstrcil L.A., Tare M., Novak J., Dragomir N., Ramirez R.J., Wlodek M.E., Conrad K.P., and Parry L.J. Relaxin mediates uterine artery compliance during pregnancy and increases uterine blood flow. FASEB J. 26:4035-44, 2012.
McGuane J.T., Debrah J.E., Sautina L., Rubin J.P., Novak J., Segal M.S. and Conrad K.P. Relaxin induces rapid dilation of rodent small renal and human subcutaneous arteries via PI3 kinase and nitric oxide. Endocrinol. 152:2786-96, 2011.
McGuane J.T., Danielson L.A., Debrah J.E., Rubin J.P., Novak J. and Conrad K.P. Angiogenic growth factors are new players in the sustained relaxin vasodilatory pathway in rodents and humans. Hypertension 57:1151-60, 2011.
Conrad K.P. 2010 Ernest H. Starling Lectureship. Maternal vasodilation in pregnancy: the emerging role of relaxin. Am J Physiol. Regulatory Integrative Comp. Physiol. 301:R267-275, 2011 (Invited Review).
Conrad K.P. Unveiling the vasodilatory actions and mechanisms of relaxin. Hypertension 56:2-9, 2010 (Invited Review).
Jeyabalan A., and Conrad K.P. Renal Physiology and Pathophysiology in Pregnancy. In: Renal and Electrolyte Disorders. 7th edition. RW Schrier, ed. Lippincott Williams & Wilkins, Chapter 13, p. 462-518, 2010.
Founds S.A., Conley Y.P., Lyons-Weiler J.F., Jeyabalan A., Hogge W.A. and Conrad K.P. Altered global gene expression in first trimester placentas of women destined to develop preeclampsia. Placenta 30: 15-24, 2009.
Rajakumar A., Jeyabalan A., Markovic N., Ness R., Gilmore C. and Conrad K.P. Placental HIF-1α, HIF-2α, membrane and soluble VEGF receptor-1 proteins are not increased in normotensive pregnancies complicated by late onset intrauterine growth restriction. Am. J. Physiol. Regulatory Integrative Comp. Physiol. 293: R766-74, 2007.
Smith M.C., Murdoch A.P., Danielson L.A., Conrad K.P. and Davison J.M. Relaxin has a role in establishing a renal response in pregnancy. Fertility and Sterility 86:253-255, 2006.
*Smith M.C., Danielson L.A., Conrad K.P. and Davison J.M. Influence of recombinant human relaxin on renal haemodynamics in humans. J. Am. Soc. Nephrol. 17: 3192-7, 2006.
Novak J., Parry L.J., Matthews J., Kerchner L.J., Indovina K., Hanley-Yanez K., Doty K.D., Debrah D.O., Shroff S.G. and Conrad K.P. Evidence for local relaxin ligand-receptor expression and function in arteries. FASEB J. 20: 2352-62, 2006.
Debrah D.O., Novak J., Matthews J.E., Ramirez R.J., Shroff S.G. and Conrad K.P. Relaxin is essential for systemic vasodilation and increased global arterial compliance during early pregnancy in conscious rats. Endocrinol. 147: 5126-31, 2006.
Debrah D.O., Conrad K.P., Jeyabalan A., Danielson L.A. and Shroff S.G. Relaxin increases cardiac output and reduces systemic arterial load in hypertensive rats. Hypertension 46:745-750, 2005.
Conrad K.P. and Novak J. The emerging role of relaxin in renal and cardiovascular function. Am. J. Physiol. 287:R250-R261, 2004 (Invited Review).
Conrad K.P., Debrah D.O., Novak J., Danielson L.A. and Shroff S.G. Relaxin modifies systemic arterial resistance and compliance in conscious, nonpregnant rats. Endocrinol. 145:3289-3296, 2004.
Jeyabalan A., Novak J., Danielson L.A., Kerchner L.J., Opett S.L. and Conrad K.P. Essential role for vascular gelatinase activity in relaxin-induced renal vasodilation, hyperfiltration, and reduced myogenic reactivity of small arteries. Circ. Res. 93:1249-1257, 2003.
Benyo D.F., Smarason A., Redman C.W.G., Sims C. and Conrad K.P. Expression of inflammatory cytokines in placentas from women with preeclampsia. J. Clin. Endocrinol. Metab. 86:2505-2512, 2001.
Novak J., Danielson L.A., Kerchner L.A., Sherwood O.D., Ramirez R.J., Moalli P.A. and Conrad K.P. Relaxin is essential for renal vasodilation during pregnancy in conscious rats. J. Clin. Invest. 107:1469-1475, 2001.
*Danielson L.A. Sherwood O.D. and Conrad K.P. Relaxin is a potent renal vasodilator in conscious rats. J. Clin. Invest. 103:525-533,1999.
Conrad K.P., Gandley R.E., Ogawa T., Nakanishi S. and Danielson L.A. Endothelin mediates renal vasodilation and hyperfiltration during pregnancy in chronically instrumented conscious rats. Am. J. Physiol. 276 (Renal Physiol. 45): F767-F776, 1999.
Conrad K.P., Kerchner L.J. and Mosher M.D. Plasma and 24-hour urinary NOx and cGMP in normal pregnancy and preeclampsia in women on a reduced-NOx diet. Am. J. Physiol. 277 (Renal Physiol. 46): F48-F57, 1999.
Conrad K.P. and Benyo D.F. Placental cytokines and the pathogenesis of preeclampsia. Am. J. Reprod. Immunol. 37:240-249, 1997 (Invited Review).
Conrad K.P., Benyo D.F., Westerhausen-Larson A. and Miles T.M. Expression of erythropoietin by the human placenta. FASEB J. 10:760-768,1996.
Danielson L.A. and Conrad K.P. Prostaglandins maintain renal vasodilation and hyperfiltration during chronic nitric oxide synthase blockade in conscious pregnant rats. Circ. Res. 79:1161-1166,1996.
*Danielson L.A. and Conrad K.P. Acute blockade of nitric oxide synthase inhibits renal vasodilation and hyperfiltration during pregnancy in chronically instrumented conscious rats. J. Clin. Invest. 96:482-490,1995.
Conrad K.P., Joffe G.M., Kruszyna H., Kruszyna R., Rochelle L.G., Smith R.P., Chavez J.E. and Mosher M.D. Identification of increased nitric oxide biosynthesis during pregnancy in rats. FASEB J. 7:566-571,1993.
Conrad K.P., Vill M., McGuire P.G., Dail W.G. and Davis A.K. Expression of nitric oxide synthase by syncytiotrophoblast in human placental villi. FASEB J. 7:1269-1276,1993.
Gilson G.J., Mosher M.D. and Conrad K.P. Systemic hemodynamics and oxygen transport during pregnancy in chronically instrumented, conscious rats. Am. J. Physiol. 263 (Heart Circ. Physiol. 32): H1911-H1918, 1992.
Conrad K.P., Barrera S.A., Friedman P.A. and Schmidt V.M. Evidence for attenuation of myo-inositol uptake, phosphoinositide turnover and inositol phosphate production in aortic vasculature of rats during pregnancy. J. Clin. Invest. 87:1700-1709,1991.
Conrad K.P. and Vernier K.A. Plasma level, urinary excretion and metabolic production of cGMP during gestation in rats. Am. J. Physiol. 257 (Regulatory Integrative Comp. Physiol. 26): R847-R853, 1989.
Conrad K.P. and Colpoys M.C. Evidence against the hypothesis that prostaglandins are the vasodepressor agents of pregnancy. Serial studies in chronically instrumented, conscious rats. J. Clin. Invest.77: 236-245, 1986.
Conrad K.P. Renal hemodynamics during pregnancy in chronically catheterized, conscious rats. Kidney Int. 26:24-29,1984.
*These works received an Editorial or Commentary.
For additional publications and current grant support, see Biosketch.
2013, 2014 – University of Florida College of Medicine: Exemplary Teacher Award
2012 – Dutch Heart Foundation Lecturer
2010 – Ernest H. Starling Distinguished Lectureship of the American Physiological Society
Water & Electrolyte Homeostasis Section
2010 – Liley Lecturer Perinatal Research Society
2010 – Senior Faculty Research Award University of Florida Chapter Sigma XI