Vascular dimorphism ensured by regulated proteoglycan dynamics favors rapid umbilical artery closure at birth
- Cleveland Clinic Lerner Research Institute, United States
- Yale University, United States
- Case Western Reserve University, United States
- Yale University School of Engineering and Applied Science, United States
- Lund University, Sweden
- Cardiff University, United Kingdom
- University of Chicago, United States
- Cleveland Clinic, United States
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
-
Human umbilical cord artery inner tunica media vs outer tunica media.Dryad Digital Repository, doi:10.5061/dryad.4j0zpc88k.
-
Human umbilical cord artery vs veinDryad Digital Repository, doi:10.5061/dryad.hdr7sqvfs.
Article and author information
Author details
Funding
National Institutes of Health (HL107147)
- Suneel S Apte
National Institutes of Health (HL141130)
- Suneel S Apte
American Heart Association (17DIA33820024)
- Suneel S Apte
Sabrina's Foundation (None)
- Elliot H Philipson
National Children's Study (Formative Research Project L01-3-RT-01-E,Contract # HHSN272500800009C)
- Martina Veigl
- David Sedwick
Mark Lauer Pediatric Research Grant (None)
- Sumeda Nandadasa
National Institutes of Health (CA43703)
- Martina Veigl
Swedish Heart-Lung Foundation (None)
- Karin Tran-Lundmark
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols: 18-1996 and 18-2045 (Cleveland Clinic IACUC), 2018-11508 (Yale University IACUC) and 43751 (University of Chicago IACUC).
Human subjects: Human umbilical cord samples were collected under an IRB exemption (EX-0118) from Cleveland Clinic for use of discarded tissue without patient identifiers. These cords were used for histological/immunohistologic analysis, in situ hybridization, and transcriptomics of inner vs outer umbilical artery TM. For microarray analysis of umbilical cord artery versus vein, human umbilical cords were collected separately through the National Children's Study under University Hospitals-Case Medical Center approved IRB protocol 01-11-28.
Copyright
© 2020, Nandadasa et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,803
- views
-
- 262
- downloads
-
- 14
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Vascular dimorphism ensured by regulated proteoglycan dynamics favors rapid umbilical artery closure at birth
eLife 9:e60683.
https://doi.org/10.7554/eLife.60683
Further reading
-
- Biochemistry and Chemical Biology
- Computational and Systems Biology
The spike protein is essential to the SARS-CoV-2 virus life cycle, facilitating virus entry and mediating viral-host membrane fusion. The spike contains a fatty acid (FA) binding site between every two neighbouring receptor-binding domains. This site is coupled to key regions in the protein, but the impact of glycans on these allosteric effects has not been investigated. Using dynamical nonequilibrium molecular dynamics (D-NEMD) simulations, we explore the allosteric effects of the FA site in the fully glycosylated spike of the SARS-CoV-2 ancestral variant. Our results identify the allosteric networks connecting the FA site to functionally important regions in the protein, including the receptor-binding motif, an antigenic supersite in the N-terminal domain, the fusion peptide region, and another allosteric site known to bind heme and biliverdin. The networks identified here highlight the complexity of the allosteric modulation in this protein and reveal a striking and unexpected link between different allosteric sites. Comparison of the FA site connections from D-NEMD in the glycosylated and non-glycosylated spike revealed that glycans do not qualitatively change the internal allosteric pathways but can facilitate the transmission of the structural changes within and between subunits.
-
- Computational and Systems Biology
In eukaryotes, protein kinase signaling is regulated by a diverse array of post-translational modifications, including phosphorylation of Ser/Thr residues and oxidation of cysteine (Cys) residues. While regulation by activation segment phosphorylation of Ser/Thr residues is well understood, relatively little is known about how oxidation of cysteine residues modulate catalysis. In this study, we investigate redox regulation of the AMPK-related brain-selective kinases (BRSK) 1 and 2, and detail how broad catalytic activity is directly regulated through reversible oxidation and reduction of evolutionarily conserved Cys residues within the catalytic domain. We show that redox-dependent control of BRSKs is a dynamic and multilayered process involving oxidative modifications of several Cys residues, including the formation of intramolecular disulfide bonds involving a pair of Cys residues near the catalytic HRD motif and a highly conserved T-loop Cys with a BRSK-specific Cys within an unusual CPE motif at the end of the activation segment. Consistently, mutation of the CPE-Cys increases catalytic activity in vitro and drives phosphorylation of the BRSK substrate Tau in cells. Molecular modeling and molecular dynamics simulations indicate that oxidation of the CPE-Cys destabilizes a conserved salt bridge network critical for allosteric activation. The occurrence of spatially proximal Cys amino acids in diverse Ser/Thr protein kinase families suggests that disulfide-mediated control of catalytic activity may be a prevalent mechanism for regulation within the broader AMPK family.
