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2018 ; 115
(28
): E6467-E6476
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Targeting ?1-integrin inhibits vascular leakage in endotoxemia
#MMPMID29941602
Hakanpaa L
; Kiss EA
; Jacquemet G
; Miinalainen I
; Lerche M
; Guzmán C
; Mervaala E
; Eklund L
; Ivaska J
; Saharinen P
Proc Natl Acad Sci U S A
2018[Jul]; 115
(28
): E6467-E6476
PMID29941602
show ga
Loss of endothelial integrity promotes capillary leakage in numerous diseases,
including sepsis, but there are no effective therapies for preserving endothelial
barrier function. Angiopoietin-2 (ANGPT2) is a context-dependent regulator of
vascular leakage that signals via both endothelial TEK receptor tyrosine kinase
(TIE2) and integrins. Here, we show that antibodies against ?1-integrin decrease
LPS-induced vascular leakage in murine endotoxemia, as either a preventative or
an intervention therapy. ?1-integrin inhibiting antibodies bound to the vascular
endothelium in vivo improved the integrity of endothelial cell-cell junctions and
protected mice from endotoxemia-associated cardiac failure, without affecting
endothelial inflammation, serum proinflammatory cytokine levels, or TIE receptor
signaling. Moreover, conditional deletion of a single allele of endothelial
?1-integrin protected mice from LPS-induced vascular leakage. In endothelial
monolayers, the inflammatory agents thrombin, lipopolysaccharide (LPS), and IL-1?
decreased junctional vascular endothelial (VE)-cadherin and induced actin stress
fibers via ?1- and ?5-integrins and ANGPT2. Additionally, ?1-integrin inhibiting
antibodies prevented inflammation-induced endothelial cell contractility and
monolayer permeability. Mechanistically, the inflammatory agents stimulated
ANGPT2-dependent translocation of ?5?1-integrin into tensin-1-positive fibrillar
adhesions, which destabilized the endothelial monolayer. Thus, ?1-integrin
promotes endothelial barrier disruption during inflammation, and targeting
?1-integrin signaling could serve as a novel means of blocking pathological
vascular leak.
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