Vascular dimorphism ensured by regulated proteoglycan dynamics favors rapid umbilical artery closure at birth.

Sumeda Nandadasa,Miriam S Domowicz,Jason M Szafron,Jay D Humphrey,Bruce Caterson,Martina Veigl,Vai Pathak,David Sedwick,Elliot H Philipson,Karin Tran-Lundmark,Suneel S Apte,Anna O'Donnell,Christian Norvik,Clare Hughes,Caroline M Kraft,Nancy B Schwartz,Sae-Il Murtada

doi:10.7554/elife.60683

Abstract

The umbilical artery lumen closes rapidly at birth, preventing neonatal blood loss, whereas the umbilical vein remains patent longer. Here, analysis of umbilical cords from humans and other mammals identified differential arterial-venous proteoglycan dynamics as a determinant of these contrasting vascular responses. The umbilical artery, but not the vein, has an inner layer enriched in the hydrated proteoglycan aggrecan, external to which lie contraction-primed smooth muscle cells (SMC). At birth, SMC contraction drives inner layer buckling and centripetal displacement to occlude the arterial lumen, a mechanism revealed by biomechanical observations and confirmed by computational analyses. This vascular dimorphism arises from spatially regulated proteoglycan expression and breakdown. Mice lacking aggrecan or the metalloprotease ADAMTS1, which degrades proteoglycans, demonstrate their opposing roles in umbilical vascular dimorphism, including effects on SMC differentiation. Umbilical vessel dimorphism is conserved in mammals, suggesting that differential proteoglycan dynamics and inner layer buckling were positively selected during evolution.

Highlights

The umbilical cord, typically containing two arteries and one vein in humans, is a crucial fetal structure in placental mammals
The distribution of chondroitin sulfate (CS) coincided with Alcian blue staining (Figure 1c–d, Figure 1—figure supplement 1e), whereas heparan sulfate was more abundant in the outer arterial tunica media (TM) (Figure 1d), suggesting that the inner TM was enriched in CS-proteoglycans (CSPGs)
We report two distinct umbilical cord blood vessel specializations that may facilitate rapid umbilical artery occlusion at birth: a distinct proteoglycan-rich inner arterial TM, generating a bilayered arterial wall, and selective contraction of smooth muscle cells (SMC) in the outer layer (Figure 8)

Summary

Introduction

The umbilical cord, typically containing two arteries and one vein in humans, is a crucial fetal structure in placental mammals. Umbilical arteries carry fetal blood to the placental vascular bed, whereas the umbilical vein returns oxygenated blood to the fetus. Neonatal respiration at birth renders the maternal oxygen supply redundant. Umbilical arteries commence closure rapidly after delivery of the newborn whereas the veins remain open longer. The cord is routinely clamped following delivery and divided between the clamps in modern obstetric practice. Timing of cord clamping after birth, whether early or late, is extensively debated (Niermeyer, 2015; Tarnow-Mordi et al, 2017).

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