Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=28476918
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
Endothelial cAMP deactivates ischemia-reperfusion-induced microvascular
hyperpermeability via Rap1-mediated mechanisms
#MMPMID28476918
Korayem AH
; Mujica PE
; Aramoto H
; Durán RG
; Nepali PR
; Kim DD
; Harris AL
; Sánchez FA
; Durán WN
Am J Physiol Heart Circ Physiol
2017[Jul]; 313
(1
): H179-H189
PMID28476918
show ga
Approaches to reduce excessive edema due to the microvascular hyperpermeability
that occurs during ischemia-reperfusion (I/R) are needed to prevent muscle
compartment syndrome. We tested the hypothesis that cAMP-activated mechanisms
actively restore barrier integrity in postischemic striated muscle. We found,
using I/R in intact muscles and hypoxia-reoxygenation (H/R, an I/R mimic) in
human microvascular endothelial cells (HMVECs), that hyperpermeability can be
deactivated by increasing cAMP levels through application of forskolin. This
effect was seen whether or not the hyperpermeability was accompanied by increased
mRNA expression of VEGF, which occurred only after 4 h of ischemia. We found that
cAMP increases in HMVECs after H/R, suggesting that cAMP-mediated restoration of
barrier function is a physiological mechanism. We explored the mechanisms
underlying this effect of cAMP. We found that exchange protein activated by cAMP
1 (Epac1), a downstream effector of cAMP that stimulates Rap1 to enhance cell
adhesion, was activated only at or after reoxygenation. Thus, when Rap1 was
depleted by small interfering RNA, H/R-induced hyperpermeability persisted even
when forskolin was applied. We demonstrate that 1) VEGF mRNA expression is not
involved in hyperpermeability after brief ischemia, 2) elevation of cAMP
concentration at reperfusion deactivates hyperpermeability, and 3) cAMP activates
the Epac1-Rap1 pathway to restore normal microvascular permeability. Our data
support the novel concepts that 1) different hyperpermeability mechanisms operate
after brief and prolonged ischemia and 2) cAMP concentration elevation during
reperfusion contributes to deactivation of I/R-induced hyperpermeability through
the Epac-Rap1 pathway. Endothelial cAMP management at reperfusion may be
therapeutic in I/R injury.NEW & NOTEWORTHY Here, we demonstrate that 1)
stimulation of cAMP production deactivates ischemia-reperfusion-induced
hyperpermeability in muscle and endothelial cells; 2) VEGF mRNA expression is not
enhanced by brief ischemia, suggesting that VEGF mechanisms do not activate
immediate postischemic hyperpermeability; and 3) deactivation mechanisms operate
via cAMP-exchange protein activated by cAMP 1-Rap1 to restore integrity of the
endothelial barrier.
free
free
free
