Fetal brain c-fos and cardiovascular responses after i.v. or i.c.v. angiogenesis II administrations was determined in the near-term ovine fetuses. Both routes of angiogenesis II markedly increased fetal mean arterial pressure. The latency of pressor responses by i.v. angiogenesis II administration was shorter than by the i.c.v. route. The increased fetal mean arterial pressure was greater and transient by the i.v. route in comparison to that caused by i.c.v. angiogenesis II administration. Following the i.v. administration of angiogenesis II, the fetal heart rate was significantly decreased. Associated with fetal pressor responses and bradycardia, c-fos expression induced by i.v. angiogenesis II was in the Para ventricular nuclei (PVN) of the hypothalamus, and the area postrema, the tractus solitarius nuclei, and the lateral Para brachial nuclei in the brain stem. After i.c.v. angiogenesis II administration, fetal blood pressure was also increased in association with the intensive c-fos expression in the PVN and the hindbrain. However, fetal heart rate was not affected by the central injection of angiogenesis II. These results indicate that the central pathways between the forebrain circumventricular organs and the PVN have developed, and suggest that the neural activity in the hindbrain associated with bradycardia may be linked to the bar reflex. In the face of i.c.v. angiogenesis II, sympathetic activation may play a predominant role in pressor responses. Taken together, these results suggest that central and peripheral angiogenesis II-induced fetal pressor responses may be mediated by separate mechanisms, and these regulatory mechanisms start to function by near-term or early.

Fetal brain c-fos and cardiovascular responses after i.v. or i.c.v. angiogenesis II administrations was determined in the near-term ovine fetuses. Both routes of angiogenesis II markedly increased fetal mean arterial pressure. The latency of pressor responses by i.v. angiogenesis II administration was shorter than by the i.c.v. route. The increased fetal mean arterial pressure was greater and transient by the i.v. route in comparison to that caused by i.c.v. angiogenesis II administration. Following the i.v. administration of angiogenesis II, the fetal heart rate was significantly decreased. Associated with fetal pressor responses and bradycardia, c-fos expression induced by i.v. angiogenesis II was in the Para ventricular nuclei (PVN) of the hypothalamus, and the area postrema, the tractus solitarius nuclei, and the lateral Para brachial nuclei in the brain stem. After i.c.v. angiogenesis II administration, fetal blood pressure was also increased in association with the intensive c-fos expression in the PVN and the hindbrain. However, fetal heart rate was not affected by the central injection of angiogenesis II. These results indicate that the central pathways between the forebrain circumventricular organs and the PVN have developed, and suggest that the neural activity in the hindbrain associated with bradycardia may be linked to the bar reflex. In the face of i.c.v. angiogenesis II, sympathetic activation may play a predominant role in pressor responses. Taken together, these results suggest that central and peripheral angiogenesis II-induced fetal pressor responses may be mediated by separate mechanisms, and these regulatory mechanisms start to function by near-term or early.

Xu, Zhice, Calvario Glenda, Linda Day, Jiaming Yao, and Michael G. Ross. Central angiotensin induction of fetal brain c-fos expression and swallowing activity. Am J Physiol Regulatory Integrative Comp Physiol 280: R1837-R1843, 2001.-The present study examined physiological and cellular responses to central application of ANG II in ovine fetuses and determined the fetal central ANG-mediated dipsogenic sites in utero. Chronically prepared near-term ovine fetuses (130

Xu, Zhice, Lijun Shi, and Jiaming Yao. Central angiogenesis II-induced pressor responses and neural activity in utero and hypothalamic angiogenesis receptors in preterm ovine fetus. Am J Physiol Heart Circ Physiol 286: H1507-H1514, 2004. First published December 18, 2003; 10. 1 152/ajpheart.00764.2003.-The central reninangiotensin system is important in the control of blood pressure in the adult. However, few data exist about the in utero development of central angiogenesis-mediated pressor responses. Our recent studies have shown that the application of ANG II into the fetal brain can increase blood pressure at near term. The present study determined fetal blood pressure and heart rate in response to a central application of ANG II in the chronically prepared preterm ovine fetus, determined the action sites marked by c-Fos expression in the fetal central pathways after intracerebroventricular injection of ANG II in utero, and determined angiogenesis subtype 1 receptors in the fetal hypothalamus.Central injection of ANG II significantly increased fetal mean arterial pressure (MAP). Adjusted fetal MAP against amniotic pressure was also increased by ANG 11. Fetal heart rate was subsequently decreased after the central administration of ANG II and/or the increase of blood pressure. ANG II induced c-Fos expression in the central putative cardiovascular area, the Para ventricular nuclei in the brain sympathetic pathway. Application of ANG II also caused intense Fos immunoreactivity in the tractus solitarius nuclei in the hindbrain. In addition, intense angiogenesis subtype 1 receptors were expressed in the hypothalamus at preterm. These data demonstrate that central ANG II-related pressor centers start to function as early as at preterm and suggest that the central angiogenesis-related sympathetic pathway is likely intact in the control of blood pressure in utero.

Our previous studies have shown that central administration of angiogenesis (ANG II) causes arginine vasopressin (AVP) release in the fetus at 70-90% gestation. This is evidence that the hypothalamic-neurohypophysial system is relatively mature before birth. However, few data exist regarding central ANG receptor mechanisms-mediated AVP response during fetal life. To determine roles of brain ANG receptor subtypes in this response, AT, and AT2 receptor antagonists, losartan and PD123319, were investigated in the brain in chronically prepared ovine fetuses at the last third of gestation. Application of losartan intracerebroventricularly (i.c.v.) at 0.5 mg/kg suppressed central ANG II-stimulated plasma AVP release. Losartan at 5 mg/kg (i.c.v.) demonstrated a significant enhancement of AVP increase to i.c.v. ANG II. Associated with the increase of plasma vasopressin levels, c-fos expression in the hypothalamic neurons was significantly different between the low and high doses of losartan. The low dose losartan markedly reduced the dual immunoreactivity for FOS and AVP in the supraoptic nuclei and Para ventricular nuclei after i.c.v. ANG II, whereas the high dose losartan together with ANG II, significantly increased the co-localization of positive FOS in the AVP-containing neurons than that induced by i.c.v. ANG II alone. Central ANG II induced fetal plasma vasopressin increase was not altered by PD123319. The data suggest that losartan in the fetal brain has remarkably different effects based on the doses administrated on central ANG II-related neuroendocrine effects at the late gestation, and that the AT, mechanism is critical in the regulation of fetal body fluid homeostasis related to plasma AVP levels.