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2284 Part XII: Hemostasis and Thrombosis Chapter 134: Atherothrombosis: Disease Initiation, Progression, and Treatment 2285

L-Selectin, Monocyte Evidence indicates that vascular smooth muscle cells that undergo
integrins apoptosis, especially at the shoulder region of the plaque, may cre-
VCAM-1, ate a more unstable cap. Both intact vascular smooth muscle cells
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LDL E-Selectin, ICAM-1
P-Selectin and fibroblasts are thought to stabilize plaques through modulation of
extracellular calcification and formation of a fibrocalcific plaque.
MCP-1 Intima Vascular smooth muscle cells arise primarily from the medial layer
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OxLDL and are considered monoclonal in origin. Evidence also indicates that
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vascular smooth muscle cells may originate from the adventitia. The
M-CSF rate and timing of smooth muscle cell replication is unclear. It may
occur at a constant low rate throughout the development of the ath-
Macrophage
activation & division erosclerotic lesion or episodically at a higher rate. Animal studies indi-
cate that new intimal cells may originate from outside the vessel wall
from subpopulations of marrow- and non–marrow-derived circulating
Media cells. Smooth muscle progenitor cells circulating in blood may con-
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Smooth muscle cell tribute to the arterial remodeling that occurs after angioplasty and after
migration bypass graft surgery. 58
Figure 134–3. Atherosclerotic lesion initiation is stimulated by oxi- Vascular proliferation and inflammation are linked processes.
dized low-density lipoprotein (OxLDL). Induction of inflammatory gene Inflammation-induced impaired NO bioactivity contributes to vascular
2
products in vascular cells is activated by the transcription factor nuclear smooth muscle proliferation. Overexpression of NO synthase results
factor-κB, which results in increased expression of cellular adhesion mol- in reduction of atherosclerotic or restenotic lesion formation in rabbits
ecules. The adhesion molecules have specific functions for endothelial through both inhibition of vascular smooth muscle cell proliferation
leukocyte interaction. The selectins tether and trap monocytes and and inhibition of adhesion and chemoattractant molecule expression,
other leukocytes. Vascular cell adhesion molecule-1 (VCAM-1) and intra- with subsequent reduction of vascular mononuclear cell infiltration.
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cellular adhesion molecule-1 (ICAM-1) mediate firm attachment of these Thus, the vascular smooth muscle cell participates in the atherosclerotic
leukocytes to the endothelial layer. OxLDL also augments expression
of monocyte chemoattractant protein-1 (MCP-1 or CCL2) and macro- process by affecting lipoprotein retention, modulating inflammation,
phage colony-stimulating factor (M-CSF). MCP-1 mediates the attrac- and controlling plaque stability through formation of the fibrous cap.
tion of monocytes and leukocytes and facilitates diapedesis through Several vascular disorders involve vascular smooth muscle proliferation
the endothelium into the intima. M-CSF is an important cytokine for the as the primary pathophysiologic mechanism, including in-stent rest-
transformation of monocytes to macrophage foam cells. Macrophages enosis, transplant vasculopathy, and vein bypass graft failure. The con-
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express scavenger receptors and internalize oxidized low-density lipo- trol of smooth muscle proliferation is thought to involve NR4A nuclear
protein (LDL) during their transformation into foam cells. Smooth mus- receptors that are expressed in atherosclerotic lesion macrophages,
cle cells migrate from the media into the intima and participate in the smooth muscle cells, and endothelial cells, and are induced by athero-
formation of a fibrous atheroma. (Adapted with permission from S Kinlay, genic stimuli. Inhibition of the transcriptional activity of the NR4A
AP Selwyn, P Libby: Inflammation, the endothelium, and the acute coronary nuclear receptors results in enhanced smooth muscle proliferation.
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syndromes. J Cardiovasc Pharmacol 32[Suppl 3]:S62, 1998.)

Figure 134–4. Vascular smooth muscle cells mediate vascular proliferation, inflammation, matrix composition, and contraction. Many of these
mediators have multiple functions. For example, angiotensin is a vasoconstrictor, but it also stimulates proliferation and inflammation. This is only a
partial list of mediators secreted by vascular smooth muscle cells. bFGF, Basic fibroblast growth factor; EGF, epidermal growth factor; G-CSF, granu-
locyte colony-stimulating factor; GM-CSF, granulocyte-monocyte colony-stimulating factor; ICAM, intracellular adhesion molecule; IGF, insulin-like
growth factor; MCP, monocyte chemoattractant protein; MMPs, matrix metalloproteinases; PAI, plasminogen-activator inhibitor; PDGF, platelet-
derived growth factor; TGF-β, transforming growth factor-β; TIMP, tissue inhibitor of metalloproteinases; TNF, tumor necrosis factor; uPA, urokinase-
type plasminogen activator; VCAM, vascular cell adhesion molecule. (Adapted with permission from Dzau VJ, Braun-Dullaeus RC, Sedding DG: Vascular
proliferation and atherosclerosis: New perspectives and therapeutic strategies. Nat Med 8(11):1249–1256, 2002.)

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