Spiral artery associated restricted growth (SPAARG): a computer model of pathophysiology resulting from low intervillous pressure having fetal programming implications  N.J. Sebire, V. Jain, D.G. Talbert  Pathophysiology  Volume 11, Issue 2, Pages 87-94 (October 2004) DOI: 10.1016/j.pathophys.2004.06.003 Copyright © 2004 Elsevier Ireland Ltd Terms and Conditions

Fig. 1 Interpretation and adaptation of the fetal lamb polyhydramnios model of Anderson and Faber [13] to human hemochorial placentation. Angiotensin-1 is released to maintain mean blood pressure, and is converted in the fetus to vasoconstrictive Ang-2. In the placental venules and veins it is converted to vasodilative Ang-7. The resultant fall in villous capillary mean pressure induces water to enter the fetal circulation until fetal blood volume is restored. Then fetal release of Ang-1 is restored to normal and net water transfer again becomes near zero although exchange flow is many litres per day. Pathophysiology 2004 11, 87-94DOI: (10.1016/j.pathophys.2004.06.003) Copyright © 2004 Elsevier Ireland Ltd Terms and Conditions

Fig. 2 Physiological aspects of placental cotyledonal structures incorporated in the model. (a) Fetal vasculature of a cotyledon showing the elements of the fetal placenta incorporated in the placental model. (b) Maternal blood flow features and relationships (arrowed path). Maternal blood enters each cotyledon through a spiral artery (SA) producing a pressure (Pcore) in the centre space. It then flows outward between the villi to the “lake” surrounding the cotyledon, pressure (Plake) and down to enter the uterine venous system (Ut.V) and out through the main uterine veins at pressure (Putv). There is a gradient of intervillous pressure from core to lake which is handled mathematically as if there were three concentric layers of villi, inner, middle and outer. This provides a further two intermediate intervillous pressures (Puiv2) and (Puiv3) for calculating water movement. Spiral artery resistances are manipulated as if in vivo an adjustable occlusive ligature was placed around the mouth of each spiral artery (Occl). A hypothetical therapeutic inflatable cuff might be placed around the uterine veins (Cuff) to raise intervillous pressure. Pathophysiology 2004 11, 87-94DOI: (10.1016/j.pathophys.2004.06.003) Copyright © 2004 Elsevier Ireland Ltd Terms and Conditions

Fig. 3 Model screen display of pressures, flows and oxygen status in sector 1 (for details see appendix; Umba: umbilical arteries; Chora: chorionic artery; Stma: stem artery; T.Vill: terminal villi; Spir A.: spiral artery; RAD: radial artery supplying myometrium and a spiral artery; Arcuate: arcuate artery supplying this placental sector; UTR.V: uterine vein; XVW: exchange rate of water through villous walls between maternal and fetal bloods for individual cotyledonal layers; PVC: villous capillary pressure (adjusted for COP); X: net exchange rate for all three layers of this cotyledon, Nt: net transfer across this cotyledon. Pathophysiology 2004 11, 87-94DOI: (10.1016/j.pathophys.2004.06.003) Copyright © 2004 Elsevier Ireland Ltd Terms and Conditions

Fig. 4 Model behaviour during progressive occlusion of spiral arteries. All nine spiral arteries were changed simultaneously to the same value. The new resistance of the spiral arteries is shown as a ratio of normal resistance at top of each vertical dashed line. The parameters shown are: (a) total fetal vascular volume (Qtot); (b) transplacental water movement (dWplac); (c) urine production (dUr); (d) mean terminal villi intracapillary hydrostatic pressure (Ptvill12 (thick trace)); (e) mean intervillous pressure (Puiv112); (f) relative secretion of fictensin to arbitrary scale and (g) fetal COP relative to a value normal to the fetus model under normal starting conditions. Pathophysiology 2004 11, 87-94DOI: (10.1016/j.pathophys.2004.06.003) Copyright © 2004 Elsevier Ireland Ltd Terms and Conditions

Fig. 5 (a–c) Electrical equivalent circuit of one of three identical sectors of the nine cotyledon dynamic placenta model. (Paort: fetal abdominal aortic pressure; Rumba: combined umbilical artery flow resistance; Rchora: chorionic artery flow resistance; Rstma: stem artery flow resistance; Rinta: intermediate villous artery resistance; Rtvcap: terminal villi flow resistance, Rintv: intermediate villous vein resistance; Rstmv: stem vein flow resistance; Rchorv: chorionic vein flow resistance; Rumbv: umbilical vein flow resistance (cord and intra fetal components); fictensin: sites of action of fictensin1 and 7 and Occl: site of hypothetical experimental occlusive cuffs in model used to restrict flow in each spiral artery. Pathophysiology 2004 11, 87-94DOI: (10.1016/j.pathophys.2004.06.003) Copyright © 2004 Elsevier Ireland Ltd Terms and Conditions