Adiponectin deficiency increases leukocyte-endothelium interactions via upregulation of endothelial cell adhesion molecules in vivo.
This study reports on what we believe are novel mechanism(s) of the vascular protective action of adiponectin. We used intravital microscopy to measure leukocyte-endothelium interactions in adiponectin-deficient (Ad(-/-)) mice and found that adiponectin deficiency was associated with a 2-fold increase in leukocyte rolling and a 5-fold increase in leukocyte adhesion in the microcirculation. Measurement of endothelial NO (eNO) revealed that adiponectin deficiency drastically reduced levels of eNO in the vascular wall. Immunohistochemistry demonstrated increased expression of E-selectin and VCAM-1 in the vascular endothelium of Ad(-/-) mice. Systemic administration of the recombinant globular adiponectin domain (gAd) to Ad(-/-) mice significantly attenuated leukocyte-endothelium interactions and adhesion molecule expression in addition to restoring physiologic levels of eNO. Importantly, prior administration of gAd also protected WT mice against TNF-alpha-induced leukocyte-endothelium interactions, indicating a pharmacologic action of gAd. Mechanistically, blockade of eNOS with N(omega)-nitro-L-arginine methyl ester ( L-NAME) abolished the inhibitory effect of gAd on leukocyte adhesion, demonstrating the obligatory role of eNOS signaling in the antiinflammatory action of gAd. We believe this is the first demonstration that gAd protects the vasculature in vivo via increased NO bioavailability with suppression of leukocyte-endothelium interactions. Overall, we provide evidence that loss of adiponectin induces a primary state of endothelial dysfunction with increased leukocyte-endothelium adhesiveness.
Ouedraogo
Raogo
R
Division of Endocrinology, Diabetes, and Metabolic Diseases, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107-6799, USA.
Gong
Yulan
Y
Berzins
Brett
B
Wu
Xiandong
X
Mahadev
Kalyankar
K
Hough
Kelly
K
Chan
Lawrence
L
Goldstein
Barry J
BJ
Scalia
Rosario
R
D052242:Adiponectin / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D019040:E-Selectin / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D036904:Leukocyte Rolling / Q000187:drug effects / Q000502:physiology; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D052242:Adiponectin; C499919:Adipoq protein, mouse; D019040:E-Selectin; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1; D009569:Nitric Oxide