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

Abstract

<jats:title>Abstract</jats:title><jats:p>The umbilical artery lumen occludes rapidly at birth, preventing blood loss, whereas the umbilical vein remains patent, providing the newborn with a placental infusion. Here, we identify differential arterial-venous proteoglycan dynamics as a determinant of these contrasting vascular responses. We show that the umbilical artery, unlike 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 elicited by biomechanical and computational analysis. Vascular dimorphism arises from spatially regulated proteoglycan expression and breakdown in umbilical vessels. Mice lacking aggrecan or the metalloprotease ADAMTS1, which degrades proteoglycans, demonstrated their opposing roles in umbilical cord arterial-venous dimorphism and contrasting effects on SMC differentiation. Umbilical vessel dimorphism is conserved in mammals, suggesting that their differential proteoglycan dynamics were a positive selection step in mammalian evolution.</jats:p>

Keratin filaments mediate the expansion of extra‐embryonic membranes in the post‐gastrulation mouse embryo

“…Using a polygenic score, we defined a small subpopulation of Primordial Germ Cells (PGC) within the Primitive Streak cluster (Fig EV5F), providing a snapshot of the PGC expression profile while in the allantois and highlighting the need to combine multiple markers, as none appeared PGC‐specific. Allantois mesenchyme had high Versican (Vcan) expression, compatible with the importance of proteoglycans in protecting blood vessels in the umbilical cord (Nandadasa et al , 2020). Vasculogenesis has been described to start at the distal end of the allantois and to progress proximally (Inman & Downs, 2006).…”

Aggrecan in Cardiovascular Development and Disease

“…4 Recent work from our group shows that aggrecan accumulation in the umbilical artery, which does not occur in the umbilical vein, is developmentally and evolutionarily ensured by robust arterial ACAN transcription and limited aggrecan degradation. 134 Computational analysis suggested that abundant aggrecan in the inner umbilical artery tunica media could promote rapid closure of this vessel at birth. 134 Furthermore, both Acan cmd-bc/cmd-bc embryos and mice lacking ADAMTS1, the most highly expressed Figure 3.…”

“…134 Computational analysis suggested that abundant aggrecan in the inner umbilical artery tunica media could promote rapid closure of this vessel at birth. 134 Furthermore, both Acan cmd-bc/cmd-bc embryos and mice lacking ADAMTS1, the most highly expressed Figure 3. Cellular impact of aggrecan accumulation in vascular smooth muscle cells (VSMC).…”

“…proteoglycan-degrading enzyme in the umbilical vein, have a severely altered VSMC phenotype. 134 There is thus a definite possibility that aggrecan accumulation around VSMCs may lead to phenotype modulation in disease ( Fig. 3) and perhaps even compromise their survival in the setting of TAAD, such as via induction of anoikis.…”

Severing umbilical ties

“…Now, in eLife, Suneel Apte (Cleveland Clinic Lerner Research Institute), Jay Humphrey (Yale University) and colleagues – including Sumeda Nandadasa as first author – report new insights into how the anatomy and physiology of the umbilical vessels facilitate rapid umbilical closure ( Nandadasa et al, 2020 ). The researchers – who are based at institutes in the US, UK and Sweden – used a multi-disciplinary approach to examine the morphological and molecular properties of umbilical blood vessels.…”