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J Am Coll Cardiol, 2007; 50:351-358, doi:10.1016/j.jacc.2007.03.046 (Published online 6 July 2007).
© 2007 by the American College of Cardiology Foundation
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A New Intra-Arterial DeliveryPlatform for Pro-Arteriogenic Compounds to Stimulate Collateral Artery Growth Via Transforming Growth Factor-ß1 Release

Sebastian Grundmann, MD*,1, Niels van Royen, MD, PhD*,1, Gerard Pasterkamp, MD, PhD{dagger}, Nieves Gonzalez, PhD{ddagger},2, Edze J. Tijsma, PhD{ddagger},2, Jan J. Piek, MD, PhD* and Imo E. Hoefer, MD, PhD*,{dagger},*

* Department of Cardiology, AMC, University of Amsterdam, Amsterdam, the Netherlands
{dagger} Laboratory of Experimental Cardiology, UMC, University of Utrecht, Utrecht, the Netherlands
{ddagger} Medtronic Bakken Research Center, Maastricht, the Netherlands.


Figure 1
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  		Figure 1 Microsphere-Based Assessment of Collateral Conductance

Implantation of transforming growth factor (TGF)-ß1–eluting stents resulted in a significant increase in collateral conductance compared with animals receiving a bolus infusion of TGF-ß1 (bolus), a bare-metal stent (BMS), or a stent coated with the polymer only (PDLLA).

 

Figure 2
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  		Figure 2 VSMC Proliferation in Collateral Arteries and Angiography of the Collateral Circulation

(A) Vascular smooth muscle cell (VSMC) proliferation in collateral arteries. In a double staining of alpha smooth muscle actin (green) and Ki67-protein for visualization of actively proliferating cells, the percentage of Ki67 positive nuclei (red) of all nuclei (blue) was quantified. Ki67 is a specific marker for proliferating cells, and only growing collateral arteries stain positive, whereas quiescent anastomoses from the non-occluded hindlimb remain negative. Collateral arteries from TGF-ß1–treated animals revealed a significantly higher index of vascular proliferation compared with the control groups, corresponding to the increase in functional conductance. (B) Angiography of the collateral circulation 7 days after stent implantation. After stent implantation in the external iliac artery (arrow), the site of vascular access in the superficial femoral artery was occluded by double ligation (*). Quantification of detectable collateral arteries with a stem, midzone, and re-entry demonstrated a weak trend toward a higher number of collaterals in the TGF-ß1–treated group. VSMC = vascular smooth muscle cell; other abbreviations as in Figure 1.

 

Figure 3
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  		Figure 3 Expression of the Adhesion Molecule Subunit CD11b on Human Monocytes

Stimulation of whole blood samples with increasing concentrations of transforming growth factor (TGF)-ß1 or TGF-ß1 from stent eluate resulted in a significant up-regulation of the integrin subunit CD11b of the monocyte adhesion molecule Mac-1. *Significant difference versus unstimulated monocytes.

 

Figure 4
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  		Figure 4 Infiltrating Macrophages in the Perivascular Space of Collateral Arteries (400x magnification)

In a double staining of alpha smooth muscle actin (green) and the macrophage marker CD68, the number of perivascular CD68+ cells was counted at a 200x magnification and expressed as cells/mm2. More CD68+ macrophages (arrows) are present in the perivascular space from TGF-ß1–treated animals compared with the control groups. Abbreviations as in Figure 1.

 

Figure 5
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  		Figure 5 Short-Term In-Stent Neointima Formation

One week after stent implantation, histological analysis of plastic embedded stents revealed a similar extent of in-stent neointima formation among the transforming growth factor (TGF)-ß1–eluting stents, bare-metal stents (BMS), and stents coated with the polymer only (PDLLA).

 




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Copyright © 2007 by the American College of Cardiology Foundation.