Quantification of angiogenesis by functional computed tomography in a Matrigel model in rats.
OBJECTIVE
The aim was to evaluate functional computed tomography (fCT) in the quantification of angiogenesis by comparing the tissue perfusion parameters measured by CT perfusion (CTP) software with histologic vascular parameters in a Matrigel model in rats. It was hypothesized that tissue perfusion parameters and histologic vascular parameters are related.


METHODS
In vivo angiogenesis assays were performed using Matrigel supplemented with escalating doses (0 ng [control group], 250 ng, and 1,000 ng) of recombinant rat vascular endothelial growth factor (VEGF164) subcutaneously injected into the backs of Sprague Dawley rats. On day 7, rats with Matrigel plug underwent fCT following a bolus injection of iodinated contrast medium. Using CTP software, fCT parameters were generated (blood flow [BF], blood volume [BV], mean transit time, and permeability-surface area product) and functional maps on the basis of a distributed parameter tracer kinetic model, the adiabatic approximation to the tissue homogeneity model. The animals were then sacrificed. Matrigel plug was sectioned into slices corresponding to the CT scan plane and stained with CD31 immunohistochemical stain. Histologic vascular parameters, including microvascular density (MVD), vessel number (VN), vascular area, and vascular perimeter, were measured. CTP and histologic parameters were correlated.


RESULTS
The Matrigel plugs with the 1,000-ng VEGF group exhibited a higher MVD than the 250-ng VEGF and control groups (P < .05). VN differed significantly between the control versus the 250-ng VEGF groups and 250-ng versus 1,000-ng VEGF groups (P < .05), with the highest VN in the 250-ng VEGF group. BF, mean transit time, and permeability-surface area product each differed significantly to VEGF levels. Changes in BF and BV did not correspond with increases in MVD or VN; however, in the 250-ng VEGF group, there was a strong positive correlation (r = 0.9) between BV and VN, vascular area, and vascular perimeter, which was not seen in the control or 1,000-ng VEGF group. All fCT parameters significantly correlated with each other (P < .05), with strong correlations between BF and mean transit time (r = -0.7) and between BF and permeability-surface area product (r = 0.7) and a weak correlation between BF and BV (r = 0.3).


CONCLUSIONS
These results validate the VEGF-induced endothelial cell in a rat Matrigel model. In addition, histologic vascular parameter MVD does not correlate with fCT parameters measured by CTP software.
Phongkitkarun
Sith
S
Division of Diagnostic Imaging, Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Unit 57, 1515 Holcombe Blvd, Houston, TX 77030-4009, USA.
Kobayashi
Satoshi
S
Kan
Zuxing
Z
Lee
Ting-Yim
TY
Charnsangavej
Chusilp
C
D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage; D000818:Animals; D003094:Collagen; D004195:Disease Models, Animal; D004338:Drug Combinations; D005109:Extracellular Matrix; D007797:Laminin; D008297:Male; D008833:Microcirculation / Q000000981:diagnostic imaging / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging* / Q000209:etiology / Q000473:pathology; D011509:Proteoglycans; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage; D014057:Tomography, X-Ray Computed; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage
D043925:Angiogenesis Inducing Agents; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; C059485:matrigel; D003094:Collagen