Low flow enhances platelet activation after acute experimental arterial injury

AbstractPurpose: Vascular smooth muscle cell (VSMC) proliferation and migration to the subintima or intimal hyperplasia (IH) occur after arterial injury and are thought to be induced by mitogenic factors released from activated platelets. Because low flow (LF) and shear have been attributed to the localization and progression of IH, we postulated that hemodynamic factors may regulate the degree of platelet activation, as measured by plasma thromboxane B2 (TXB2) and platelet-derived growth factor-AB (PDGF-AB) release at regions of experimental arterial injury. Methods: The right common carotid artery (CCA) was subjected to balloon injury in 18 New Zealand White male rabbits. Flow in the injured CCA was reduced by out-flow ligation (LF group, n = 6) or increased by ligation of the left CCA (high flow [HF] group, n = 6). In six other animals, flow was preserved (normal flow [NF] group). Mean blood flow and pressure in the right CCA were measured thereafter at 10 and 30 minutes. Plasma TXB2 and PDGF-AB levels were determined with the enzyme-linked immunosorbent assay method in each animal with blood samples taken systematically before injury (baseline) and in the distal CCA at similar time points. Results: At 10 minutes, mean blood flow was reduced from 20 ± 2 ml/min in the NF group to 7 ± 1 ml/min in the LF group animals (p < 0.01) and increased to 32 ± 2 ml/min in the HF group animals (p < 0.05). Mean arterial blood pressure did not differ among the groups. Hemodynamic parameters were similar at 10 and 30 minutes. TXB2 levels were more than fourfold greater in the LF group than in the HF and NF groups at both time points (p < 0.05). In addition, there was a twofold increase in plasma PDGF-AB level at 10 minutes in the LF group compared with baseline levels (p < 0.05). Conclusion: Platelet activation at regions of acute vascular injury was determined to be flow dependent. Upregulated platelet activity in low flow conditions may be due to increased platelet exposure time to subendothelial collagen and is greatly attenuated if normal or increased flow is present.(J Vasc Surg 1998;27:910-8.

Role of fibrinopeptide B in early atherosclerotic lesion formation

The development of atheroselerotic lesions involves many cell types, including macrophages. Fibrinopeptide B (FPB) has been shown to be a potent chemotactic agent for macrophages, which are abundant as intimal foam cells in atherosclerotic lesions, especially in cholesterol-fed rabbits. We hypothesize that intimal low-density lipoproteins also cause fibrinogen in the intima to release FPB and that FPB attracts macrophages in response to the high lipid levels associated with lesion development. To test our hypothesis, we used an atherosclerotic model. Silk sutures containing either FPB, fibrinopeptide A (FPA), lipopolysaccharide (LPS), or saline control were prepared. One suture of each type was placed in the adventitia of the femoral artery of a rabbit. Animals were killed at 1 or 2 weeks. Only vessels exposed to either FPB or LPS showed significant intimal thickening in the region adjacent to the suture site. Semi-thin electron microscopic sections indicated that the intimal wall was highly cellular and that many cells contained lipid vacuoles after 2 weeks. These sections also showed that the endothelium remained intact and that no injury to the media of the artery had occurred. Electron microscopy of the tissue samples showed the proliferation of smooth muscle cells and deposition of extracellular matrix in the 2-week animals, whereas foam cells were present in the l-week animals. We conclude that FPB does indeed attract macrophages to the intima and that these macrophages may become foam cells. The model we have developed can be used to study possible mechanisms for the entry of macrophages into the intima during early lesion development and to further understand the complex interactions of FPB, fibrinogen, and lipids in atherosclerotic lesion development. T he development ofatherosclerotic lesions is a complex process and probably involves interactions between circulating blood elements, including serum lipids and white blood cells (e.g., monocytes and lymphocytes), and the arterial wall, including endothelial cells and smooth muscle cells of the media. The nature of this interaction and the role of blood-borne cells in this process, especially macrophages, are not completely understood. From the Departments of Surgery and Fibrinogen is a serum protein with a major role in blood clotting. It may also be the source of a chemotactic factor for the monocytes that accumulate as intimal foam cells during atherogenesis. Three considerations point to such a mechanism. First, diet-induced hyperlipemia is associated with an increased influx of ape-B-containing lipoproteins into the intima The complex process involving the interactions of fibfinogen, FPB, and lipoproteins is not fully understood. One possible mechanism is that when fibrinogen binds to lipoproteins with the requisite phospholipid surface, the lipids become oxidized so that they cannot exit the vessel wall. Since there is also a release of FPB, we hypothesize that FPB attracts macrophages to deal with the offending agent (the altered lipids). Previous studies by Prescott et al MATERIAL AND METHODS Sixteen New Zealand White rabbits (3.0 to 3.5 kg) were used. 4.0 silk sutures were prepared by soaking them 15