Our lab is interested in the mechanisms that contribute to the regulation of uteroplacental blood flow (UPBF) during pregnancy and those involved in modulating vascular development and blood pressure in the fetus and neonate. 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 in pregnancy, and in particular, the >3-fold rise in the last 3rd of pregnancy, which parallels the exponential increase in fetal weight. When UPBF does not rise, fetal growth is impaired, resulting in fetal growth restriction (FGR) and increases in fetal and neonatal morbidity and mortality. We have long studied the mechanisms that regulate UPBF in pregnancy, in particular, the role of estrogen, various vasoactive agents, including nitric oxide, alpha-agonists and angiotensin II, and more recently, the role of large conductance calcium-activated K+ channels. To accomplish these goals, we use chronically instrumented pregnant and nonpregnant sheep to perform in vivo studies of vascular function and physiology, infusing agonists and antagonists systemically or directly into the uterine circulation while continuously monitoring UPBF, heart rate and blood pressure and simultaneously collecting uterine venous and arterial blood for measurement of uterine metabolism and synthesis of vasoactive agents. We also collect tissues from these animals in order to perform in vitro studies with vascular rings, which permits us to examine cellular pathways, and frozen tissues, which allows 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 use of western immunoblots, SDS polyacrylamide gel electrophoresis, immunohistochemistry and RT-PCR. It is this integrated use of whole animal physiology and cellular and molecular biology that make our lab unique. At present, we are using this approach to determine the role of the BKCa in mediating the vasodilatory effects of estrogen, regulating basal UPBF before and during pregnancy and in attenuating uteroplacental contraction responses. We also have been able to examine changes in VSM expression of the channel pore and its regulatory beta-subunits, describing estrogen-induced changes in stoichiometry that also occur in pregnancy. These studies are now ongoing in human tissues. Similar approaches are used to study changes in VSM development and functional maturation in the ovine fetus, which has a gestation of ~150d, and neonate, which is the size of human neonate, 3-4 kg, at birth. This model permits us to instrument and study the fetus in utero throughout pregnancy, which cannot be done with other species, and to collect sufficient quantities of tissue, vascular and nonvascular, for studies using the techniques outlined above to examine cellular changes and signaling pathways. There is a large library of maternal, fetal and neonatal vascular tissues maintained for future studies of receptor and nonreceptor protein and mRNA expression. Parallel studies of neonates have been designed 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
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
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, In Press
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, "Distribution of cardiac output in ovine pregnancy." Am J Physiol, 232:H231-H235, 1977
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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