Prenatal Programming of Pulmonary Hypertension Induced by Chronic Hypoxia or Ductal Ligation in Sheep

Abstract

Pulmonary hypertension of the newborn is caused by a spectrum of functional and structural abnormalities of the cardiopulmonary circuit. The existence of multiple etiologies and an incomplete understanding of the mechanisms of disease progression have hindered the development of effective therapies. Animal models offer a means of gaining a better understanding of the fundamental basis of the disease. To that effect, a number of experimental animal models are being used to generate pulmonary hypertension in the fetus and newborn. In this review, we compare the mechanisms associated with pulmonary hypertension caused by two such models: in utero ligation of the ductus arteriosus and chronic perinatal hypoxia in sheep fetuses and newborns. In this manner, we make direct comparisons between ductal ligation and chronic hypoxia with respect to the associated mechanisms of disease, since multiple studies have been performed with both models in a single species. We present evidence that the mechanisms associated with pulmonary hypertension are dependent on the type of stress to which the fetus is subjected. Such an analysis allows for a more thorough evaluation of the disease etiology, which can help focus clinical treatments. The final part of the review provides a clinical appraisal of current treatment strategies and lays the foundation for developing individualized therapies that depend on the causative factors.

Fetal programming and its effects on vascular pulmonary circulation

“…Mechanisms and pathways identified using apposite PHN models hypoxia models, in functional reductions in soluble guanylyl cyclase (sGC) function, cyclic guanosine monophosphate (cGMP)-dependent vasorelaxation, increased phosphodiesterase type 5 (PDE5) and enhanced Endothelin-1 (ET-1) contraction. In contrast, significant differences were found in the cellular processes between the two models: a significant decrease in the levels of endothelial nitric oxide synthase (eNOS) and calcium activated potassium channels (BKCa) in ligation models; an increase of these molecules in chronic hypoxia [22] . Other models for PHN are the exposure-based models, including short-term neonatal hyperoxia, fetal and/or post-natal hypoxia and a two-hit model of prenatal hypoxia followed by postnatal hyperoxia.…”

“…Of note are the experimental investigations on animal models, given the inadequate availability of patient tissues and inability to perform mechanistic studies in humans. Several animal PH's models have been developed for performing studies into the functional and structural changes, which occur during the development of pulmonary circulation and PH [21][22][23][24][25][26][27][28][29][30][31][32][33][34] . Unfortunately, to date not a single preclinical model perfectly replicates human PH.…”

“…Some relevant models for PHN have been developed and studied. Of note are the results obtained by the utero ligation of the ductus arteriosus and chronic perinatal hypoxia in sheep fetuses and newborns [22] . They have demonstrated that the mechanisms associated with PH are dependent on the type and grade of stress to which the fetus is subjected [22] .…”

“…Of note are the results obtained by the utero ligation of the ductus arteriosus and chronic perinatal hypoxia in sheep fetuses and newborns [22] . They have demonstrated that the mechanisms associated with PH are dependent on the type and grade of stress to which the fetus is subjected [22] . Specifically, similarities were observed between the ligation and End-products of endothelial-derived nitric oxide (NO) heme-oxidation, nitrate and nitrite produce exogenous NO, which mediates an increased vasoactive signaling activity during hypoxia and stress Alteration in maternal microbiome Table 1.…”

Physiological and Biochemical Consequences of Exposure of Neonatal Rats to Chronic Hypoxia

“…Etiologies of pulmonary hypertension of the neonate are varied and they are not clearly understood, but the condition is marked by a high morbidity and mortality of the presenting newborns. [26][27][28] Chronic in utero exposure to high altitude environment 13,16 and epigenetic factors 29 are some natural causative factors of neonatal pulmonary hypertension. Among other things, the data presented here show that chronic hypoxia exposure alone is sufficient to induce neonatal pulmonary hypertension in support of existing information and further show, for the first time, that chronic neonatal hypoxia exposure contributes to increase in pulmonary vascular tone of newborns.…”