Our lab is interested in the mechanisms contributing to the regulation of uteroplacental (UPBF) and umbilicoplacental (UMBF) blood flow during pregnancy and those involved in modulating vascular development and blood pressure in the fetus and neonate. Normal fetal growth and well-being are dependent on the delivery of nutrients and oxygen from the maternal circulation, which depend on the >30-fold rise in UPBF and UMBF in pregnancy, and in particular, the >3-fold rise in the last 3rd of pregnancy, which parallels an exponential rise in fetal weight. When UPBF or UMBF do not increase, fetal growth is impaired, resulting in fetal growth restriction (FGR), increases in fetal and neonatal morbidity and mortality, and a risk for early onset hypertension and metabolic syndrome. We continue to study the mechanisms that regulate UPBF in pregnancy, in particular, the role of estrogen, vasoactive agents including nitric oxide, alpha-agonists and angiotensin II, and the role of K+ channels, in particular, large conductance Ca2+-activated K+ channels. We are now examining the role of K+ channels in modulating the fetal-placental circulation. To accomplish these goals, we use chronically instrumented pregnant and nonpregnant sheep to perform studies of vascular function and physiology, infusing agonists and antagonists systemically or directly into the uterine or umbilical circulations while continuously monitoring blood flow, heart rate and blood pressure and simultaneously collecting uterine/umbilical venous and arterial blood to examine uterine metabolism and synthesis of vasoactive agents. Tissues are collected from these animals to perform studies with vascular rings, which permits us to examine cellular pathways, and frozen tissues, which allow us to examine changes in expression of endothelial/smooth muscle vascular receptors, cellular proteins, enzymes and mRNA, e.g., smooth muscle contractile and cytoskeletal proteins, nitric oxide synthases and membrane mediators, including specific K+ channels (BKCa)and their signaling pathways. The latter include western immunoblots, SDS polyacrylamide gel electrophoresis, immunohistochemistry and RT-PCR. Because of this integrated approach to whole animal physiology and cellular and molecular biology, our lab is rather unique. We are using this approach to study the role of BKCa in estrogen-mediated vasodilation, the regulation of basal UPBF and UMBF during normal pregnancy and in the presence of hyperglycemia, and to understand the attenuated vascular contraction responses normal to pregnant women and sheep. To date, we have 1) characterized the changes in VSM expression of the BKCa pore and its regulatory beta-subunits during pregnancy and the ovarian cycle, 2) described estrogen-induced changes in channel stoichiometry, 3) shown channel expression and function in human uterine arteries, and 4) provided preliminary data that BKCa contribute to UMBF. Studies are ongoing in human tissues as well as the ewe. Similar approaches are used to study changes in VSM development and functional maturation in the ovine fetus, which has a gestation of ~150d and is the size of human neonate, 3-4 kg, at term. This model permits us to instrument and study the fetus throughout pregnancy, which cannot be achieved in other species, and to collect sufficient quantities of vascular and nonvascular tissue for studies of cellular changes and signaling pathways. There also is an extensive library of maternal, fetal and neonatal vascular tissues maintained at -80C for future studies of receptor and nonreceptor protein and mRNA expression. Parallel studies of the newborn human are underway to complement the animal studies described and as noted above, human tissues are available for study of vascular changes in pregnancy.
RESEARCH INTERESTS
Mechanisms modulating uteroplacental blood flow
Development of the renin-angiotensin system
Cardiovascular role of estrogen in pregnancy
Blood pressure regulation before and after birth
RECENT PUBLICATIONS
Rosenfeld CR, Word RA, DeSpain K, Liu X-t., "Large conductance Ca+2-activated K+ channels contribute to vascular function in nonpregnant human uterine arteries." Reprod Sciences, 15:651-660, 2008
Cox BE, Liu X, Fluharty, SJ, Rosenfeld CR, "Vessel-specific regulation of angiotensin II receptor subtypes during ovine development." Pediatr Res, 57:124-132, 2005
Velaphi SC, DeSpain K, Roy T, and Rosenfeld CR, "The renin-angiotensin system in conscious newborn sheep: metabolic clearance rate and activity." Pediatr Res, 61:681-686, 2007
Hutuna, C, Cox BE, Liu X-t, DeSpain, K and Rosenfeld CR, "Vascular development beginning in early ovine gestation: carotid smooth muscle function, phenotype and biochemical markers." Am J Physiol: Regulatory Integrative Comp Physiol, 293:323-333, 2007
SIGNIFICANT PUBLICATIONS
Naden RP and Rosenfeld CR, "Effect of angiotensin II on uterine and systemic vasculature in pregnant sheep." J Clin Invest, 68:468-474, 1981
Cox BE and Rosenfeld CR, "Ontogeny of vascular angiotensin II receptor subtype expressin in ovine development." Pediatr Res, 45:414-424, 1999
Rosenfeld CR, Morris FH, Jr., Makowski EL, Meschia G, and Battaglia FC., "Circulatory changes in the reproductive tissues of ewes during pregnancy." Gynecol Invest, 5:252-268, 1974
Rosenfeld CR, , Liu X-t, and DeSpain K, "Pregnancy modifies the large conductance Ca2+-activated K+ channel expression and cGMP-dependent signaling pathway in uterine vascular smooth muscle" Am J Physiol: Heart Circ Physiol, In press June 2009
Rosenfeld CR, Cornfield DN, and Roy T, "Ca2+ -activated K+channels modulate basal and E2 -induced rises in uterine blood flow in ovine pregnancy." Am J Physiol: Heart Circ Physiol, 281:H22-H31, 2001
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