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 ,
Nieves Gonzalez, PhD ,2,
Edze J. Tijsma, PhD,2,
Jan J. Piek, MD, PhD* and
Imo E. Hoefer, MD, PhD*,,*
* Department of Cardiology, AMC, University of Amsterdam, Amsterdam, the Netherlands
Laboratory of Experimental Cardiology, UMC, University of Utrecht, Utrecht, the Netherlands
Medtronic Bakken Research Center, Maastricht, the Netherlands.
View larger version (15K):
[in this window]
[in a new window]
[Download PPT slide]
|
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).
|
|
View larger version (62K):
[in this window]
[in a new window]
[Download PPT slide]
|
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.
|
|
View larger version (15K):
[in this window]
[in a new window]
[Download PPT slide]
|
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.
|
|
View larger version (73K):
[in this window]
[in a new window]
[Download PPT slide]
|
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.
|
|
View larger version (84K):
[in this window]
[in a new window]
[Download PPT slide]
|
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).
|
|
|
