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Frontiers in endocrinology2019; 10; 667; doi: 10.3389/fendo.2019.00667

The Interaction Between Nodal, Hypoxia-Inducible Factor 1 Alpha, and Thrombospondin 1 Promotes Luteolysis in Equine Corpus Luteum.

Abstract: The regulation of corpus luteus (CL) luteolysis is a complex process involving a myriad of factors. Previously, we have shown the involvement of Nodal in functional luteolysis in mares. Presently, we ask the extent of which Nodal mediation of luteolysis is done through regulation of angioregression. We demonstrated the interaction between Nodal and hypoxia-inducible factor 1 α (HIF1α) and thrombospondin 1/thrombospondin receptor (TSP1/CD36) systems, could mediate angioregression during luteolysis. First, we demonstrated the inhibitory effect of Nodal on the vascular marker platelet/endothelial cell adhesion molecule 1 (CD31). Also, treatment of mid CL explants with vascular endothelial growth factor A (VEGFA) showed a trend on activin-like kinase 7 (Alk7) protein inhibition. Next, Nodal was also shown to activate HIF1α and culture of mid CL explants under decreased oxygen level promoted Nodal expression and SMAD family member 3 (Smad3) phosphorylation. In another experiment, the crosstalk between Nodal and TSP1/CD36 was investigated. Indeed, Nodal increased the expression of the anti-angiogenic TSP1 and its receptor CD36 in mid CL explants. Finally, the supportive effect of prostaglandin F2α (PGF2α) on TSP1/CD36 was blocked by SB431542 (SB), a pharmacological inhibitor of Nodal signaling. Thus, we evidenced for the first time the interaction between Nodal and both HIF1α and TSP1 systems, two conserved pathways previously shown to be involved in vascular regression during luteolysis. Considering the given increased expression of Nodal in mid CL and its role on functional luteolysis, the current results suggest the additional involvement of Nodal in angioregression during luteolysis in the mare, particularly in the activation of HIF1α and TSP1/CD36.
Copyright © 2019 Walewska, Wołodko, Skarzynski, Ferreira-Dias and Galvão.
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Publication Date: 2019-10-01 PubMed ID: 31632347PubMed Central: PMC6779822DOI: 10.3389/fendo.2019.00667Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research article discusses the role of the protein Nodal in the breakdown of the corpus luteum in horses, suggesting that Nodal likely influences this process indirectly through its interactions with two other biological systems, hypoxia-inducible factor 1 α (HIF1α) and thrombospondin 1/thrombospondin receptor (TSP1/CD36).

Introduction

  • The regulation of the degradation of corpus luteum, a structure integral to the menstrual cycle and pregnancy, is complex and involves many factors. This study builds on previous work demonstrating the role of the Nodal protein in this process.
  • The researchers aimed to discover the extent of Nodal’s role in angioregression – the regression of blood vessels – during luteolysis, the breakdown of the corpus luteum. They focused on the interactions between Nodal and two other biological systems, HIF1α and TSP1/CD36.

Methods and Results

  • The team used various experimental approaches to study the effects of Nodal on markers related to blood vessel formation. It was shown that Nodal inhibits the vascular marker CD31 and potentially decreases Alk7 protein when the corpus luteum is exposed to VEGFA, a major regulator of blood vessel formation.
  • They also determined Nodal’s effect on the activation of HIF1α, a key player in cellular responses to low oxygen conditions (hypoxia). When the corpus luteum was cultured in low-oxygen conditions, the expression of Nodal and the phosphorylation of Smad3, a protein involved in relaying Nodal signals, were increased.
  • The research further explored the interaction between Nodal and the TSP1/CD36 system, which is involved in inhibiting angiogenesis (formation of new blood vessels). Nodal was found to increase the expression of TSP1 and its receptor CD36.
  • Additionally, the study observed the effects of a pharmacological inhibitor of Nodal signalling, SB431542 (SB), which effectively blocked the influence of prostaglandin F2α (PGF2α), a hormone known to support TSP1/CD36.

Conclusion

  • This study provides evidence for the interaction of Nodal with both the HIF1α and TSP1 systems, which are involved in regulating blood vessel regression during luteolysis.
  • Given the increased expression of Nodal in mid corpus luteum and its previously demonstrated role in functional luteolysis, these results suggest an expanded role for Nodal in angioregression during luteolysis, particularly in the activation of HIF1α and TSP1/CD36.

Cite This Article

APA
Walewska E, Wołodko K, Skarzynski D, Ferreira-Dias G, Galvão A. (2019). The Interaction Between Nodal, Hypoxia-Inducible Factor 1 Alpha, and Thrombospondin 1 Promotes Luteolysis in Equine Corpus Luteum. Front Endocrinol (Lausanne), 10, 667. https://doi.org/10.3389/fendo.2019.00667

Publication

Frontiers in endocrinology
ISSN: 1664-2392
NlmUniqueID: 101555782
Country: Switzerland
Language: English
Volume: 10
Pages: 667
PII: 667

Researcher Affiliations

Walewska, Edyta
  • Department of Reproductive Immunology and Pathology, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland.
Wołodko, Karolina
  • Department of Reproductive Immunology and Pathology, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland.
Skarzynski, Dariusz
  • Department of Reproductive Immunology and Pathology, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland.
Ferreira-Dias, Graça
  • The Centre for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Lisbon, Portugal.
Galvão, António
  • Department of Reproductive Immunology and Pathology, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland.

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Citations

This article has been cited 4 times.
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