Quantifying angiogenesis in VEGF-enhanced tissue-engineered bladder constructs by dynamic contrast-enhanced MRI using contrast agents of different molecular weights

Purpose: 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. Materials and 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: vp provided the best distinction (P < 0.005), but both vp and AUC were correlated to MVD. With Gd-DTPA, only AUC distinguished MVD differences (P < 0.05). Changes in K-trans were insignificant. Conclusion: 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.