Testisin/Prss21 deficiency causes increased vascular permeability and a hemorrhagic phenotype during luteal angiogenesis.
Animals
Antigens, CD
/ metabolism
Cadherins
/ metabolism
Capillary Permeability
/ genetics
Cells, Cultured
Corpus Luteum
/ blood supply
Female
GPI-Linked Proteins
/ antagonists & inhibitors
Gene Knockdown Techniques
Hemorrhage
/ etiology
Humans
Luteinization
/ genetics
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Neovascularization, Physiologic
/ genetics
Phenotype
Serine Endopeptidases
/ deficiency
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2020
2020
Historique:
received:
04
03
2020
accepted:
24
05
2020
entrez:
9
6
2020
pubmed:
9
6
2020
medline:
29
8
2020
Statut:
epublish
Résumé
Testisin (encoded by PRSS21) is a membrane anchored serine protease, which is tethered to the cell surface via a glycosylphosphatidylinositol (GPI)-anchor. While testisin is found in abundance in spermatozoa, it is also expressed in microvascular endothelial cells where its function is unknown. Here we identify testisin as a novel regulator of physiological hormone-induced angiogenesis and microvascular endothelial permeability. Using a murine model of rapid physiological angiogenesis during corpus luteal development in the ovary, we found that mice genetically deficient in testisin (Prss21-/-) show a substantially increased incidence of hemorrhages which are significantly more severe than in littermate control Prss21+/+ mice. This phenotype was associated with increased vascular leakiness, demonstrated by a greater accumulation of extravasated Evans blue dye in Prss21-/- ovaries. Live cell imaging of in vitro cultured microvascular endothelial cells depleted of testisin by siRNA knockdown revealed that loss of testisin markedly impaired reorganization and tubule-like formation on Matrigel basement membranes. Moreover testisin siRNA knockdown increased the paracellular permeability to FITC-albumin across endothelial cell monolayers, which was associated with decreased expression of the adherens junction protein VE-cadherin and increased levels of phospho(Tyr658)-VE-cadherin, without affecting the levels of the tight junction proteins occludin and claudin-5, or ZO-1. Decreased expression of VE-cadherin in the neovasculature of Prss21-/- ovaries was also observed without marked differences in endothelial cell content, vascular claudin-5 expression or pericyte recruitment. Together, these data identify testisin as a novel regulator of VE-cadherin adhesions during angiogenesis and indicate a potential new target for regulating neovascular integrity and associated pathologies.
Identifiants
pubmed: 32511276
doi: 10.1371/journal.pone.0234407
pii: PONE-D-20-06406
pmc: PMC7279603
doi:
Substances chimiques
Antigens, CD
0
Cadherins
0
GPI-Linked Proteins
0
cadherin 5
0
PRSS21 protein, human
EC 3.4.21.-
Prss21 protein, mouse
EC 3.4.21.-
Serine Endopeptidases
EC 3.4.21.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0234407Subventions
Organisme : BLRD VA
ID : I01 BX001921
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA196988
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL118390
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007698
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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