Quantifying angiogenesis in VEGF-enhanced tissue-engineered bladder constructs by dynamic contrast-enhanced MRI using contrast agents of different molecular weights.
OBJECTIVE
To compare Gadomer, a macromolecular magnetic resonance (MR) contrast agent, and gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) for quantifying angiogenesis in tissue-engineered bladder constructs.


METHODS
Constructs enhanced with vascular endothelial growth factor (VEGF) were grafted onto the bladder of 12 rabbits (N= 3/VEGF, VEGF = 0,10,15,20 ng/g tissue). After eight days dynamic contrast-enhanced MRI (DCE-MRI) was performed in each animal using Gadomer and Gd-DTPA, separated by a one-hour interval. DCE-MRI parameters were calculated from two-compartment pharmacokinetics (plasma volume fraction, v(p); transfer constant, K(trans)) and model-free analysis, area under the concentration-time curve (AUC). Histology assessment of microvessel density (MVD) and Evans blue permeability were compared to DCE-MRI.


RESULTS
MVD was elevated (P < 0.05) at the highest VEGF but not among lower levels; permeability differences were absent. Contrast enhancement increased with VEGF and was better resolved with Gadomer than Gd-DTPA. Gadomer was the better assay for estimating plasma volume: v(p) provided the best distinction (P < 0.005), but both v(p) and AUC were correlated to MVD. With Gd-DTPA, only AUC distinguished MVD differences (P< 0.05). Changes in K(trans) were insignificant.


CONCLUSIONS
Macromolecular contrast agents are valuable for monitoring angiogenesis in tissue-engineered bladder grafts. Compared to Gd-DTPA, Gadomer provides more accurate and precise quantification of microvessel function, and is better suited to pharmacokinetic analysis for accurate physiological quantification.
Cheng
Hai-Ling Margaret
HL
Department of Diagnostic Imaging, The Hospital for Sick Children, Toronto, Canada. hai-ling.cheng@sickkids.ca
Wallis
Chad
C
Shou
Zhiping
Z
Farhat
Walid A
WA
D000704:Analysis of Variance; D000818:Animals; D003287:Contrast Media / Q000737:chemistry*; D005682:Gadolinium / Q000737:chemistry*; D019786:Gadolinium DTPA / Q000737:chemistry*; D007091:Image Processing, Computer-Assisted; D046911:Macromolecular Substances; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008970:Molecular Weight; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010539:Permeability; D011817:Rabbits; D023822:Tissue Engineering; D001743:Urinary Bladder / Q000098:blood supply*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
D003287:Contrast Media; D046911:Macromolecular Substances; D042461:Vascular Endothelial Growth Factor A; C402765:gadomer 17; D005682:Gadolinium; D019786:Gadolinium DTPA