Molecular imaging of endothelial vascular cell adhesion molecule-1 expression and inflammatory cell recruitment during vasculogenesis and ischemia-mediated arteriogenesis.
BACKGROUND
Inflammatory responses contribute to vascular remodeling during tissue repair or ischemia. We hypothesized that inflammatory cell recruitment and endothelial cell activation during vasculogenesis and ischemia-mediated arteriogenesis could be temporally assessed by noninvasive molecular imaging.


RESULTS
Contrast ultrasound perfusion imaging and molecular imaging with microbubbles targeted to activated neutrophils, alpha(5)-integrins, or vascular cell adhesion molecule (VCAM-1) were performed in murine models of vasculogenesis (subcutaneous matrigel) or hind-limb ischemia produced by arterial occlusion in wild-type or monocyte chemotactic protein-1-deficient mice. In subcutaneous matrigel plugs, perfusion advanced centripetally between days 3 and 10. On targeted imaging, signal enhancement from alpha(5)-integrins and VCAM-1 coincided with the earliest appearance of regional blood flow. Targeted imaging correlated temporally with histological evidence of channel formation by alpha(5)-integrin-positive monocytes, followed by the appearance of spindle-shaped cells lining the channels that expressed VCAM-1. In ischemic hind-limb tissue, skeletal muscle blood flow and arteriolar density increased progressively between days 2 and 21 after arterial ligation. Targeted imaging demonstrated early signal enhancement for neutrophils, monocyte alpha(5)-integrin, and VCAM-1 at day 2 when blood flow was very low (<20% control). The neutrophil signal declined precipitously between days 2 and 4, whereas VCAM-1 and monocyte signal persisted to day 7. In mice deficient for monocyte chemotactic protein-1, monocyte-targeted signal was severely reduced compared with wild-type mice (1.2+/-0.6 versus 10.5+/-8.8 video intensity units on day 4; P<0.05), although flow responses were only mildly impaired.


CONCLUSIONS
Different components of the inflammatory response that participate in vascular development and remodeling can be assessed separately with targeted molecular imaging.
Behm
Carolyn Z
CZ
Division of Cardiovascular Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
Kaufmann
Beat A
BA
Carr
Chad
C
Lankford
Miles
M
Sanders
John M
JM
Rose
C Edward
CE
Kaul
Sanjiv
S
Lindner
Jonathan R
JR
D000818:Animals; D002633:Chemotaxis; D003952:Diagnostic Imaging / Q000379:methods*; D004730:Endothelium, Vascular / Q000737:chemistry / Q000502:physiology; D007249:Inflammation / Q000473:pathology*; D039482:Integrin alpha5 / Q000032:analysis; D007511:Ischemia; D051379:Mice; D045423:Microbubbles; D009000:Monocytes / Q000737:chemistry / Q000502:physiology; D018482:Muscle, Skeletal / Q000098:blood supply; D018919:Neovascularization, Physiologic; D018375:Neutrophil Activation; D012039:Regional Blood Flow; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis*
D039482:Integrin alpha5; D019010:Vascular Cell Adhesion Molecule-1