Angiotensin II is a growth factor in the peri‐implantation rat embryo

Abstract

Angiotensin II (ANG II) is increasingly recognised as a growth factor, both in its own right and through interactions with other growth factors. There is a high density of ANG II receptors in the rat fetus, especially the AT2 receptor, the function of which is still uncertain. We have now studied the effects of ANG II on growth and development in the rat embryo in vitro between d 9.5 and 11.5, and characterised the receptor subtype mediating these effects. Embryos were cultured in whole rat serum, a high molecular weight retenate after ultrafiltration of whole rat serum, retenate with angiotensin II and retenate with ANG II and AT1 or AT2 receptor blockers. Growth and development were scored using conventional methods. Culture in retenate was associated with a marked reduction in growth and development by comparison with whole rat serum. This was partly, and significantly (P 0.001), reversed by angiotensin II. The optimum concentration of angiotensin II was found to be angiotensin II 10 -"" , within the physiological range. Angiotensin II had highly significant effects on both somatic (P 0.001) and yolk sac\allantoic (P 0.005) development. The latter effects suggest a role for angiotensin II in placentation. The effects of angiotensin II were blocked by PD123319, an AT2 blocker, but not by GR117289, an AT1 blocker. Interestingly, culture in retenate with GR117289 without added angiotensin II was also associated with some increase in growth (P 0.05). Angiotensin II in low concentrations was measurable in the retenate, presumably arising from the action of endogenous renin on angiotensinogen. We therefore postulate that this effect of GR117289 was due to the action of endogenous angiotensin II on ' uncovered ' AT2 receptors. This study has thus demonstrated a direct growth promoting effect of angiotensin II during organogenesis in the whole rat embryo in vitro. This effect is mediated through the AT2 receptors.

Presynaptic Angiotensin II AT1 Receptors Enhance Inhibitory and Excitatory Synaptic Neurotransmission to Motoneurons and Other Ventral Horn Neurons in Neonatal Rat Spinal Cord

“…There is a transient up-regulation of the renin-angiotensin system in the neonatal period (Kalinyak et al 1991;Wallace et al 1980) and plasma concentration of ANG II increases transiently about fivefold in the neonatal (Wallace et al 1980). Collectively these observations support a role for angiotensin receptors in neuronal growth and development, a feature noted in various preparations, including cultured hypothalamic neurons (Jirikowski et al 1984); peri-implantation rat embryo (Tebbs et al 1999), and embryonic neurons (Ikeda et al 1989;Iwasaki et al1991;Sood et al 1990b). In addition, angiotensin belongs to a family of vasoactive and mitogenic peptides that participate in physiological and pathological cell growth and differentiation (Van Biesen et al 1996) and can activate a set of kinases that are known for their importance in cell survival (Richards et al 1999;Yang et al 2001).…”

Retinal Angiogenesis Is Mediated by an Interaction between the Angiotensin Type 2 Receptor, VEGF, and Angiopoietin

“…41 There is also evidence that the AT2 receptor promotes cell growth and inflammation in vascular smooth muscle cells, rat embryo, and cultured cells. 15,17,42 Previous studies by our laboratory have reported combined AT1-RB and AT2-RB to be more effective than monotherapy in attenuating cell proliferation and tissue injury in an experimental model of renal disease. 33 In view of the present findings, this approach is worth considering in terms of potential therapeutic strategies for the treatment of retinal angiogenesis in ROP and proliferative diabetic retinopathy.…”

Effects of Gestation on Ovine Fetal and Maternal Angiotensin Receptor Subtypes in the Heart and Major Blood Vessels

“…Therefore, although most studies have concentrated on the effects of Ang II on cardiac growth and development mediated through its AT 1 receptor, there may be an additional role for Ang II in early cardiac development mediated via the AT 2 receptor (Tebbs et al 1999). Furthermore, the treatment of rat whole embryo cultures with Ang II plus PD-123319 caused cardiac loop inversions which might be associated with disruption of myofibrillar structure (Price et al 1997).…”

“…receptor blockade had no effect (Tebbs et al 1999). It is now widely accepted that the AT 2 receptor is involved in apoptosis (Yamada et al 1996).…”