Background: Sufficient oxygen and nutrient supply to the baby is facilitated by adapting the utero-placental vasculature. Inadequate adaptation can cause fetal growth restriction, which goes undetected in ~50% of cases before birth. Uterine radial arteries (RAs) have been identified as rate-limiting for placental blood supply, but adaptation mechanisms are insufficiently studied. This work aims to combine computational and experimental approaches to understand how paracrine factors facilitate RA remodelling.
Methods: A rat uterine-specific computational model was developed, informed by direct measurements and µCT-scans (n=3/group), and used to predict RA flow rates. RA responses to increasing pressure and flow were determined in virgin and late-pregnant (E19.5) Sprague-Dawley rats (n=6-10/group) by pressure myography. Virgin RAs (n=5-6/group) were pre-incubated with estrogen, progesterone, PlGF, and/or VEGF to examine their influence on flow-mediated reactivity. Nitric oxide involvement was assessed with L-NAME.
Results: Under pressure-only conditions, inner diameters across pressure steps were significantly larger in RAs from pregnant animals (p=0.04). Both groups developed myogenic tone ≥50mmHg (in vivo pressure), with the response more pronounced in RAs from pregnant animals. Under flow, virgin and pregnant RAs constricted at predicted in vivo flow rates (11.8µl/min virgin vs. 60.4µl/min pregnant). Estrogen, progesterone, and PlGF (not VEGF), and the combination of all factors, delayed flow-mediated constriction in virgin RAs (p=0.04), enabling them to recapitulate the prolonged resistance to vasoconstriction with increasing flow rates seen in pregnancy. L-NAME inhibition of eNOS partly reduced RA reaction induced by individual paracrine factors, but this was insufficient to result in an effect when all paracrine factors were combined (p=0.95).
Conclusions: Maladaptation of RAs could cause over-sensitivity of vessels to flow, thus limiting utero-placental flow. While nitric oxide seems to be involved in the adaptation of vascular reactivity, additional mechanisms are yet to be uncovered. This will identify targets to improve vascular adaptation in the future.