title: Pravastatin stimulates angiogenesis in a murine hindlimb ischemia model: a positron emission tomography imaging study with (64)Cu-NOTA-TRC105.
abstract: In this study, (64)Cu-NOTA-TRC105 (TRC105 is an anti-CD105 monoclonal antibody that binds to both human and murine CD105) positron emission tomography (PET) was used to assess the response to pravastatin treatment in a murine model of peripheral artery disease (PAD). Hindlimb ischemia was induced by ligation of the right femoral arteries in BALB/c mice under anesthesia, and the left hindlimb served as an internal control. Mice in the treatment group were given intraperitoneal pravastatin daily until the end of the study, whereas the animals in the control group were injected with 0.9% sodium chloride solution. Laser Doppler imaging showed that blood flow in the ischemic hindlimb plummeted to ~20% of the normal level after surgery, and gradually recovered to near normal level on day 10 in the treatment group and on day 20 in the control group. Angiogenesis was non-invasively monitored and quantified with (64)Cu-NOTA-TRC105 PET on postoperative days 3, 10, 17, and 24. Tracer uptake at 48 h post-injection in the ischemic hindlimb in the treatment group was significantly higher than that of the control group on day 10 (20.5 ± 1.9 %ID/g vs 11.4 ± 1.5 %ID/g), suggesting increased CD105 expression and higher level of angiogenesis upon pravastatin treatment, and gradually decreased to background levels in both groups (4.9 ± 0.8 %ID/g vs 3.4 ± 1.9 %ID/g on day 24). The in vivo PET data correlated well with ex vivo biodistribution studies performed on day 24. Increased CD105 expression on days 3 and 10 following ischemia was further confirmed by immunofluorescence staining. Taken together, our results indicated that (64)Cu-NOTA-TRC105 PET is a suitable and non-invasive method to monitor the angiogenesis and therapeutic response in PAD, which can also be utilized for non-invasive evaluation of other pro-angiogenic/anti-angiogenic drugs in other cardiovascular diseases and cancer.
authors.affiliation: Department of Radiology, University of Wisconsin - Madison WI, USA.
authors.forename: Hakan
authors.initials: H
authors.lastname: Orbay
authors.affiliation: Department of Radiology, University of Wisconsin - Madison WI, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Hong
authors.affiliation: Department of Medicine, University of Wisconsin - Madison WI, USA.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Koch
authors.affiliation: Department of Medical Physics, University of Wisconsin - Madison WI, USA.
authors.forename: Hector F
authors.initials: HF
authors.lastname: Valdovinos
authors.affiliation: Department of Medicine, University of Wisconsin - Madison WI, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Hacker
authors.affiliation: TRACON Pharmaceuticals, Inc. San Diego, CA, USA.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Theuer
authors.affiliation: Department of Medical Physics, University of Wisconsin - Madison WI, USA.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Barnhart
authors.affiliation: Department of Radiology, University of Wisconsin - Madison WI, USA ; Department of Medical Physics, University of Wisconsin - Madison WI, USA ; University of Wisconsin Carbone Cancer Center Madison, WI, USA.
authors.forename: Weibo
authors.initials: W
authors.lastname: Cai
keywords: Angiogenesis; CD105 (endoglin); ischemia; peripheral artery disease (PAD); positron emission tomography (PET); pravastatin