Endothelial JAM-A Guides Monocytes into Flow-Dependent Predilection Sites of Atherosclerosis

Background — Junctional adhesion molecule (JAM)-A expressed in endothelial, epithelial and blood cells can regulate permeability and leukocyte extravasation. Atherosclerosis develops at sites of disturbed flow in large arteries but the mechanisms guiding inflammatory cells into these predilection sites remain unknown. Methods and Results — To characterize cell-specific functions of JAM-A in atherosclerosis, we employed apolipoprotein E-deficient mice with a somatic or endothelium-specific deficiency in JAM-A and bone marrow chimeras with JAM-A-deficient leukocytes. We show that impaired JAM-A expression in endothelial cells reduced mononuclear cell recruitment into the arterial wall and limited atherosclerotic lesion formation in hyperlipidemic mice. In contrast, JAM-A deficiency in bone marrow cells impeded monocyte de-adhesion, thereby increasing vascular permeability and lesion formation, whereas somatic JAM-A deletion revealed no significant effects. Regions with disturbed flow displayed a focal enrichment and luminal redistribution of endothelial JAM-A and were preferentially protected by its deficiency. The functional expression and redistribution of endothelial JAM-A was increased by oxidized low-density lipoprotein, but confined by atheroprotective laminar flow through an up-regulation of miR-145, which repressed JAM-A. Conclusions — Our data identify endothelial JAM-A as an important effector molecule integrating atherogenic conditions to direct inflammatory cell entry at predilection sites of atherosclerosis. ff up-eegugugulalalatititiononn aaandndn expressiiionono l ceclllss ofofof attheeerorgenic coondndnditttioonnss ooofff hyhyhypepeperlrlipippididdememmiiaa. TTheee incccreeaseeeddd lulummiinanall JJAAMM-M-AAA avavvaiaiailalabibiilililtytyty ccouuulldld memeedididiatatatee enennhahahancnceeded rrececruruititimemntntn aaandndnd hhhigigheheherr r cococontnttenenett t ooff mmmacaccrororophphphagagaeeses aaandndn TT-c-celelllslsl iiin n aatathhheroroosccclelerorrotitiic c plaques of hypypyperereliliipipipidededemimmc mimimicecee. InInI vvvitirororo eeexpxpxperererimimimenenntststs conononfififirmrmrmededed tthahaat tt oxoxoxidididizizzeded LLLDLDLDL iiincnnreased eecrrruuitment inn rreesppoponsnsse tototo mmmodododififieieedd d lilppipiddds andndnd at prprpreediilleecectitiononon ssititess wwititihhh ddidiststturururbebedd d flfllowowo. InInIncrcreaeaeased exxprprpresesessisisonon aaandnnd fffococcalal rrrededdisistrtibibbututtioioion nn oofof JJJAMAMAM--A-A cccononntrrololleled dd bybyby mechanisms tttoo o exexexplplplaiaan nn thtte e e hihihighghghererer ssususuceceeptptptibibibililiititity y y tototo aaththterrrosososclclcerererosososisisi iiin nn rereregigigiononons s s wiwiwiththth dddisisstutrbed ooff jujuuncntitiiononnaaalll adadadheheesisiiononon mmmolololececcululle e aananddd plplplattteleleeett/eeendndndootothheheliliaalal cccelell l adaddheeessioonon moolelecuculle-1-1 atat hummann vvasasccular endndototheheliliala jununctctioionsns bbyy cyyttokokinines ttumumorr necrorosiss fafactctorr-a-plus interferoon-n-ng g g dododoesese nnnoto rrredededucucce