Pharmacological activation of peroxisome proliferator-activated receptor γ (PPAR-γ) protects against hypoxia-associated fetal growth restriction.

The hypoxia of high-altitude (HA) residence increases the risk of intrauterine growth restriction (IUGR) and preeclampsia 3-fold, augmenting perinatal morbidity and mortality and the risk for childhood and adult disease. Currently, no effective therapies exist to prevent these vascular disorders of pregnancy. The peroxisome proliferator-activated receptor γ (PPAR-γ) is an important regulator of uteroplacental vascular development and function and has been implicated in the pathogenesis of IUGR and preeclampsia. Here, we used a model of HA pregnancy in mice to determine whether hypoxia-induced fetal growth restriction reduces placental PPAR-γ protein expression and placental vascularization and, if so, to evaluate the effectiveness of the selective PPAR-γ agonist pioglitazone (PIO) for preventing hypoxia-induced IUGR. Hypoxia resulted in asymmetric IUGR, placental insufficiency, and reduced placental PPAR-γ expression; PIO prevented approximately half of the fetal growth restriction and attenuated placental insufficiency. PIO did not affect fetal growth under normoxia. Although PIO was beneficial for fetal growth, PIO treatment reduced placental vascular density of the labrynthine zone in normoxic and hypoxic (Hx) conditions, and mean vascular area was reduced in the Hx group. Our results suggest that pharmacological PPAR-γ activation is a potential strategy for preventing IUGR in pregnancies complicated by hypoxia, although further studies are needed to identify its likely metabolic or vascular mechanisms.-Lane, S. L., Dodson, R. B., Doyle, A. S., Park, H., Rathi, H., Matarrazo, C. J., Moore, L. G., Lorca, R. A., Wolfson, G. H., Julian, C. G. Pharmacological activation of peroxisome proliferator-activated receptor γ (PPAR-γ) protects against hypoxia-associated fetal growth restriction.

Erythropoietin and Soluble Erythropoietin Receptor: A Role for Maternal Vascular Adaptation to High-Altitude Pregnancy.

Context: An imbalance of proangiogenic and antiangiogenic factors is thought to induce the widespread vascular dysfunction characteristic of preeclampsia (PreE). Erythropoietin (Epo), a pleiotropic cytokine, has important angiogenic and vasoactive properties; however, its contribution to maternal vascular dysfunction in PreE is unknown. Objectives: Because high altitude (HA) raises the incidence of PreE, we asked whether HA increased maternal Epo and soluble Epo receptor (sEpoR) levels and whether such effects differed between PreE and normotensive controls at HA. Design, Setting, and Participants: Longitudinal studies were conducted in pregnant Andean residents at HA (n = 28; 3600 m) or sea level (SL; n = 16; 300 m). Cross-sectional studies included 34 gestational age‒matched Andean PreE cases (n = 17) and controls (n = 17) in La Paz-El Alto, Bolivia (3600 to 4100 m). Results: HA augmented the pregnancy-associated rise in Epo relative to SL (P = 0.002), despite similar reductions in hemoglobin (Hb) across pregnancy at each altitude (7% to 9%, P < 0.001 for both). HA PreE cases had circulating Epo levels equivalent to those of controls but greater sEpoR (P < 0.05) and reduced Hb (P = 0.06, trend). Conclusion(s): Our findings suggest that an augmented pregnancy-associated rise in Epo may be important for successful vascular adaptation to pregnancy at HA. We further speculate that the elevated sEpoR observed in PreE vs controls at HA impedes the effect of Epo to maintain endothelial function and may, in turn, be of pathological relevance for PreE at HA.