Regulation of monocyte subset systemic levels by distinct chemokine receptors controls post-ischaemic neovascularization.
OBJECTIVE
Monocyte systemic levels are known to be a major determinant of ischaemic tissue revascularization, but the mechanisms mediating mobilization of different monocyte subsets-Ly6C(hi) and Ly6C(lo)-to the blood and their respective role in post-ischaemic neovascularization are not clearly understood. Here, we hypothesized that distinct chemokine/chemokine receptor pathways, namely CCL2/CCR2, CX3CL1/CX3CR1, and CCL5/CCR5, differentially control monocyte subset systemic levels, and might thus impact post-ischaemic vessel growth.


RESULTS
In a model of murine hindlimb ischaemia, both Ly6C(hi) and Ly6C(lo) monocyte circulating levels were increased after femoral artery ligation. CCL2/CCR2 activation enhanced blood Ly6C(hi) and Ly6C(lo) monocyte counts, although the opposite effect was seen in mice with CCL2 or CCR2 deficiency. CX3CL1/CX3CR1 strongly impacted Ly6C(lo) monocyte levels, whereas CCL5/CCR5 had no role. Only CCL2/CCR2 signalling influenced neovascularization, which was increased in mice overexpressing CCL2, whereas it markedly decreased in CCL2-/- mice. Moreover, adoptive transfer of Ly6C(hi)-but not Ly6C(lo)-monocytes enhanced vessel growth and blood flow recovery.


CONCLUSIONS
Altogether, our data demonstrate that regulation of proangiogenic Ly6C(hi) monocytes systemic levels by CCL2/CCR2 controls post-ischaemic vessel growth, whereas Ly6C(lo) monocytes have no major role in this setting.
Cochain
Clément
C
Paris Cardiovascular Research Center, Université Paris Descartes, UMR-S970 Paris, France.
Rodero
Mathieu P
MP
Vilar
José
J
Récalde
Alice
A
Richart
Adèle L
AL
Loinard
Céline
C
Zouggari
Yasmine
Y
Guérin
Coralie
C
Duriez
Micheline
M
Combadière
Behazine
B
Poupel
Lucie
L
Lévy
Bernard I
BI
Mallat
Ziad
Z
Combadière
Christophe
C
Silvestre
Jean-Sébastien
JS
D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D018932:Chemokine CCL2 / Q000097:blood; D018946:Chemokine CCL5 / Q000097:blood; D054428:Chemokine CX3CL1 / Q000097:blood; D002634:Chemotaxis, Leukocyte; D004195:Disease Models, Animal; D006614:Hindlimb; D007511:Ischemia / Q000276:immunology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology*; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D054390:Receptors, CCR2 / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation
D000950:Antigens, Ly; D000073883:CX3C Chemokine Receptor 1; C491768:Ccl2 protein, mouse; C503460:Ccl5 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; C471885:Cx3cr1 protein, mouse; C526827:Ly6 protein, mouse; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine