Monocyte Chemotactic Protein-1 Increases Collateral and Peripheral Conductance After Femoral Artery Occlusion

Abstract

Monocytes are activated during collateral artery growth in vivo, and monocyte chemotactic protein-1 (MCP-1) has been shown to be upregulated by shear stress in vitro. In order to investigate whether MCP-1 enhances collateral growth after femoral artery occlusion, 12 rabbits were randomly assigned to receive either MCP-1, PBS, or no local infusion via osmotic minipump. Seven days after occlusion, isolated hindlimbs were perfused with autologous blood at different pressures, measuring flows at maximal vasodilation via flow probe and radioactive microspheres, as well as peripheral pressures. This allowed the calculation of collateral (thigh) and peripheral (lower limb) conductances from pressure-flow tracings (slope of the curve). Collateral growth on postmortem angiograms was restricted to the thigh and was markedly enhanced with MCP-1 treatment. Both collateral and peripheral conductances were significantly elevated in animals with MCP-1 treatment compared with the control group, reaching values of nonoccluded hindlimbs after only 1 week of occlusion (collateral conductance, 70.6 +/- 19.23 versus 25.1 +/- 2.59 mL/min per 100 mm Hg; P < .01; peripheral conductance, 119.3 +/- 22.37 versus 45.4 +/- 6.80 mL/min per 100 mm Hg; P < .05). These results suggest that activation of monocytes plays an important role in collateral growth as well as in capillary sprouting.

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

“…7,11,12 Occlusions of large arteries (eg femoral artery 11,18 or coronary arteries 20 ) either acutely or progressively 21 are established animal models to study both angiogenesis and arteriogenesis as well as effects of therapeutic …”

“…Owing to the considerable degree of spontaneous collateralization in rabbits after arterial ligation, 18 the significant difference in size of the arteries between rabbits and humans and the difficulties in applying gene-delivery catheters originally designed for human use to small animals, this study was performed in a porcine model of PAOD. To validate the model and to define its natural time course of recovery, we studied the magnitude of collateralization following occlusion of the femoral artery without any therapeutic intervention.…”

“…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 …”

“…Therefore, a therapeutic increase of arteriogenesis appears to be desirable to restore at least part of the necessary blood flow to distal tissues. Whereas most of the growth factors examined so far mediate angiogenesis (eg VEGF, bFGF), [26][27][28][29][30] recent studies showed that MCP-1 18 and, to a lesser degree, GM-CSF 24 were able to improve arteriogenesis in rabbit models. GM-CSF elevates the local monocyte count by increasing recruitment from the bone marrow and enhancing cell survival.…”

“…6,11,12 MCP-1 is a member of the CC-chemokine family. [13][14][15][16][17] It has been shown to stimulate arteriogenesis when applied exogenously as a continuous intra-arterial infusion, resulting in a 2.5-fold increase in the magnitude of the arteriogenic response in a rabbit model 18 and in an approximately two-fold increase in a porcine model of PAOD. VEGF or other hypoxia-inducible genes (eg hypoxia-inducible factor-1a, lactate dehydrogenase A) are not associated with arteriogenesis under nonischaemic conditions.…”