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Figure 6-1: Pathways of thrombosis and thrombolysis. Under normal conditions, the endothelium is antithrombotic. Antithrombin III (ATIII) binds thrombin and serves to clear thrombin from the circulation. Prostacyclin (prostaglandin I2, PGI2) inhibits platelet aggregation, and thrombomodulin (TM) activates protein C, which inhibits plasminogen activator inhibitor I (PAI-I) and interacts with protein S to inactivate activated factors V and VIII, thus limiting thrombosis. Since PAI-I inhibits the tissue plasminogen activator (tPA)-catalyzed conversion of plasminogen to plasmin, PAI-I inhibition leads to accumulation of plasmin and fibrinolysis. Upon stimulation with inflammatory cytokines, there is increased expression of tissue factor on the endothelial cell surface. Tissue factor participates in the activation of factor X, which, in turn, promotes assembly of the prothrombinase complex, producing thrombin. Under these conditions, endothelial cells thus amplify the thrombotic response. (Courtesy of Bernard Lassegue, Ph.D.) Figure 6-2: Signaling pathways in vascular smooth muscle. Vasoconstrictor agonists interact with specific G protein-coupled receptors (GPCRs) on vascular smooth muscle. These receptors are linked to a heterotrimeric G protein (oPy), which then couples to one or more phospholipase Cs (PLCs) or phospholipase D (PLD). PLC cleaves the inositol phospholipids to yield diacylglycerol (DG) and inositol phosphates, in particular, inositol trisphosphate (IP3). IP3 releases calcium from intracellular stores, and, along with DG, activates the Ca2+- and phospholipid-dependent enzyme protein kinase C (PKC). Ca2+ activates numerous other kinases, including p21-activated kinase (OtPAK), Pyk2, and myosin light chain kinase (MLCK). PLD cleaves phosphatidylcholine to release phosphatidic acid, which is converted to DG. PKC is involved in activation of the mitogen-activated protein kinase (MAPK) cascade, including extracellular signal-regulated kinases (ERK1/2) and Jun kinase (JNK). Growth factors activate receptor tyrosine kinases (RTKs), Src, PLC-g, and phosphatidylinositol 3-kinase (PI3K). RTKs also phosphorylate and form a signaling complex with paxillin and adapter proteins such as Shc, which binds Grb-2 and Sos and ultimately mediates the conversion of Ras to its active form. Ras phosphorylates Raf1, which in turn leads to activation of the MAP Kinase cascade. Figure 6-3: Contraction cascade. Activation of smooth muscle by a vasoconstrictor hormone leads to a cascade of biochemical signals, ultimately resulting in phosphorylation of actomyosin, cross-bridge formation, and force generation. The release of Ca2+ from intracellular stores is one of the major initiating events, since Ca2+ combines with calmodulin to activate myosin light chain kinase. This enzyme phosphorylates the myosin light chain, which is then able to interact with actin. Abbreviations: R = receptor; PLC = phospholipase C; DG = diacylglycerol; PIP2 = phosphatidylinositol 4,5-bisphosphate; IP3 = inositol trisphosphate; CaM = calmodulin; MLCK = myosin light chain kinase; MLC = myosin light chain; P = phosphate. (Courtesy of Bernard Lassegue, Ph.D.)

' Figure 6-4: Endothelial control of vascular tone. Endothelial cells synthesize and secrete both vasodilator substances (NO, EDHF, and PGI2) and vasoconstrictor compounds (Ang II and ET-4). Secretion of these factors occurs in response to receptor stimulation and hemodynamic forces such as shear stress. Vessel tone depends on the balance between these factors, as well as on the ability of the smooth muscle cells to respond to them. Abbreviations: NO. = nitric oxide; NOS = nitric oxide synthase; EDHF = endothelial-derived hyperpolarizing factor; PGI2 = prostaglandin I2; ACE = angiotensin-converting enzyme; Ang = angiotensin; ET-4 = endothelin-4; cGMP = cyclic guanosine monophosphate; cAMP = cyclic adenosine monophosphate; 5-HT-5-hydroxytryptamine.

s Figure 6-5: Endothelial control of vascular growth. As with vasoactive substances, endothelial cells make and secrete both growth-promoting (white boxes) and growth-inhibitory (colored boxes) compounds. Under normal conditions, the net effect of the endothelium is growth inhibitory. Abbreviations: EDRF = endothelial-derived relaxing factor; NO = nitric oxide; TGF-P = transforming growth factor-P; PDGF = platelet-derived growth factor; IGF-I = insulin-like growth factor-I; IL-4 = interleukin-4; FGF = fibroblast growth factor. (Courtesy of Bernard Lassegue, Ph.D.)

' Figure 6-6: Effect of shear stress on endothelial cells. In bovine aortic endothelial cells grown in static conditions, F-actin filaments assume a random orientation as visualized by rhodamine-labeled phalloidin staining (left). Upon exposure to shear stress (30 dynes/cm2, 24 h), these filaments align {right). Bars = 100 Mm. (Courtesy of Lula Hilenski, Ph.D.)

' Figure 6-7: Theoretical initiating events in vascular lesion formation. Non-denuding injury: Low-density lipoprotein (LDL) enters the subendothelial space where it is converted to oxidized LDL (ox-LDL), which induces monocyte chemoattraction and endothelial dysfunction. Dysfunctional endothelial cells (ECs) express cell adhesion molecules (ICAM, ELAM, and VCAM), leading to increased monocyte adhesion and movement into the vessel wall. Monocytes in the vessel wall differentiate into macrophages, take up lipids, and remain locally as foam cells, subsequently evolving into fatty streaks. The foam cells in the fatty streak and the overlying endothelium express monocyte chemotactic protein 4 (MCP-4), resulting in further enhanced monocyte chemoattraction and adhesion. Dysfunctional ECs may synthesize less nitric oxide synthase (NOS) or superoxide dismutase (SOD, an enzyme that metabolizes oxygen radicals that have been shown to inactivate NO). This decreases endothelial-derived relaxing factor (EDRF) release/activity. The loss of EDRF together with the direct effects of ox-LDL, or growth factors secreted by the foam cells or endothelium, act on the quiescent contractile smooth muscle cells in the vessel wall, giving rise to the proliferative phenotype, with division and migration into the intima. Denuding injury: Loss of endothelium leads to platelet deposition, tissue factor-mediated activation of extrinsic coagulation to generate thrombin, cleavage of fibrinogen to fibrin, and the formation of thrombus. Thrombin gives rise to endothelial expression of adhesion molecules and consequent monocyte attachment, together with secretion of platelet granular constituents. Monocytes enter the thrombus and differentiate into phagocytic macrophages expressing tissue factor and MCP-4. This leads to further monocyte chemoattraction into the vessel wall. Smooth muscle cell proliferation is produced by (4) thrombin generation at the site of denuding injury, (2) platelet-derived growth factor (PDGF) or other growth factors released from platelets in the thrombus, (3) factors secreted by the macrophages ingesting the thrombus, and (4) the loss of EDRF activity caused by endothelial dysfunction. Proliferative response: Modulated smooth muscle cells (SMCs) proliferate and synthesize factors that promote plaque development. SMCs synthesize (4) PDGF and other growth factors that cause self-perpetuating autocrine or paracrine stimulation of SMC proliferation, (2) tissue factor (TF) and plasminogen activator inhibitor 4 (PAI-4 that act locally to produce thrombin or inhibit fibrinolysis of the fibrin network used to facilitate cell migration, and (3) MCP-4, which increases monocyte chemoattraction into the lesion, thereby leading to lesion development. (We thank Drs. Laurence Harker, Josiah Wilcox, and Bernard Lassegue for their creative and intellectual development of this figure.)

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