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2017 ; 214
(9
): 2535-2545
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Annexin A2 supports pulmonary microvascular integrity by linking vascular
endothelial cadherin and protein tyrosine phosphatases
#MMPMID28694388
Luo M
; Flood EC
; Almeida D
; Yan L
; Berlin DA
; Heerdt PM
; Hajjar KA
J Exp Med
2017[Sep]; 214
(9
): 2535-2545
PMID28694388
show ga
Relative or absolute hypoxia activates signaling pathways that alter gene
expression and stabilize the pulmonary microvasculature. Alveolar hypoxia occurs
in disorders ranging from altitude sickness to airway obstruction, apnea, and
atelectasis. Here, we report that the phospholipid-binding protein, annexin A2
(ANXA2) functions to maintain vascular integrity in the face of alveolar hypoxia.
We demonstrate that microvascular endothelial cells (ECs) from Anxa2(-/-) mice
display reduced barrier function and excessive Src-related tyrosine
phosphorylation of the adherens junction protein vascular endothelial cadherin
(VEC). Moreover, unlike Anxa2(+/+) controls, Anxa2(-/-) mice develop pulmonary
edema and neutrophil infiltration in the lung parenchyma in response to subacute
alveolar hypoxia. Mice deficient in the ANXA2-binding partner, S100A10, failed to
demonstrate hypoxia-induced pulmonary edema under the same conditions. Further
analyses reveal that ANXA2 forms a complex with VEC and its phosphatases,
EC-specific protein tyrosine phosphatase (VE-PTP) and Src homology phosphatase 2
(SHP2), both of which are implicated in vascular integrity. In the absence of
ANXA2, VEC is hyperphosphorylated at tyrosine 731 in response to vascular
endothelial growth factor, which likely contributes to hypoxia-induced
extravasation of fluid and leukocytes. We conclude that ANXA2 contributes to
pulmonary microvascular integrity by enabling VEC-related phosphatase activity,
thereby preventing vascular leak during alveolar hypoxia.