Modulation of collateral artery growth in a porcine hindlimb ligation model using MCP-1

Abstract

For an appropriate extrapolation to patients with peripheral arterial obstructive disease, we tested the efficacy of monocyte chemoattractant protein 1 (MCP-1) treatment in a porcine hindlimb ligation model. In 40 minipigs, a femoral artery ligation was performed. Control animals were examined immediately after ligation (n = 4) or after 2 wk of intra-arterial infusion of PBS (n = 11). A second group of animals was evaluated after intra-arterial infusion of 2.0 microg/h of MCP-1 for 48 h (followed by 12 days of PBS; n = 13) or 2 wk continuously (n = 12). In the terminal experiment after 2 wk, resting flow to the leg and peripheral arterial pressures were assessed without vasodilatation. Subsequently, vascular conductance was determined by using a pump-driven extracorporal circulation during maximal vasodilatation. The results showed that resting blood flow to the hindlimb was 53% of the normal after 2 wk of infusion of PBS, compared with 81% in both MCP-1 treatment groups (P < 0.05). Collateral conductance was 645 +/- 346 ml x min(-1) x mmHg(-1) after 2 wk of infusion with PBS, compared with 1,070 +/- 530 and 1,158 +/- 535 ml x min(-1) x mmHg(-1) after 48 h and 2 wk treatment with MCP-1, respectively (P < 0.05). Modulation of the process of arteriogenesis is feasible in this large animal model via intra-arterial infusion of the Cys-Cys-chemokine MCP-1.

Tissue-engineered vascular grafts transform into mature blood vessels via an inflammation-mediated process of vascular remodeling

“…In particular, significantly high levels of MCP-1 were induced by hBMC seeding (Fig. 3 C and F), which reached quantities comparable to MCP-1 levels used in prior arteriogenesis studies (12,13). Based on the levels obtained, MCP-1's known function as a potent monocyte chemokine, and its established link to postnatal neovascularization (12-15), we pursued further investigations into whether MCP-1 might be playing a role in TEVG development.…”

“…Rapid early monocyte recruitment has been shown to be intricately involved in postnatal blood vessel formation (32)(33)(34). In particular, successful arteriogenesis is dependent on MCP-1-induced monocyte recruitment to preexistent collateral arterioles (12)(13)(14)(15)35). TEVGs seem to follow a similar developmental pattern in which a short pulse of MCP-1 (derived from scaffold-activated BMCs vs. shear stress-activated ECs) enables rapid monocyte recruitment to a predetermined location of blood vessel formation (biodegradable scaffold vs. collateral arteriole).…”

Nonviral monocyte chemoattractant protein-1 gene transfer improves arteriogenesis after femoral artery occlusion

“…This is comparable to improvements of conductance mediated by continuous infusion of MCP-1 protein in rabbit and pig. 22,23 The present study showed for the first time that a nonviral gene therapeutic approach was equipotent to a protein perfusion therapy. Transfection of 2 mg MCP-1_genomic led to significant improvements of conductance and to an increase in peripheral blood pressure.…”

“…MCP-1 protein has been shown to be a potent arteriogenic stimulant when infused in the rabbit femoral artery ligation model over 8 days and in pigs over a 2-week treatment period. 17,18,22,23 Since prolonged administration of MCP-1 in a clinical setting via intraarterial application appears undesirable, a liposomebased nonviral gene transfer to achieve local MCP-1 overexpression and production was developed and …”

TNF-α and Shear Stress-Induced Large Artery Adaptations

“…Lack of these inflammatory signaling pathways abrogates outward arterial remodeling in response to increased local wall shear [10; 35]. Pro-inflammatory approaches have been offered to promote arteriogenesis, or compensatory outward remodeling [36][37][38][39]. However, a troublesome side effect of arteriogenic therapies may be acceleration of occlusive inflammatory vascular processes such as atherosclerosis [40].…”