The Cell Cycle and Proliferation

In angiogenesis, ECs undergo division through a highly controlled and orchestrated process known as the cell cycle. On binding to their receptors, growth promoters trigger an alteration of ECs from a quiescent or resting state (G0) into a replicative phase (G1); G represents "gap." During this time window (the G0/G1 phase), extracellular signals are transmitted through cytoplasmic signal cascades (see later discussion), which in turn induce nuclear responses that control progression of the cell through mitosis. Once a cell has passed a specific point in the G1 phase (after about 11 hours), it is committed to divide and enters the S phase. Once past this point the cells cycle is irreversible. The S phase is complete within 8 hours and the cell enters the G2 phase (2 hours). Finally the cell enters the M phase (1 hour) where cell replication takes place. The whole cell cycle is therefore complete within 24 hours after initial stimulation with growth promoters.

The early signal transduction pathways that trigger VSMC replication can be described as a series of protein phosphorylations that are mediated both sequentially and sometimes in parallel by protein kinases (PKs) (Figure 2). A phosphorylated protein kinase will then activate another PK through phosphorylation of that PK. It is by this means that

PDGFR/ EGFR

Figure 2 Proliferative signaling in endothelial cells originating from RTK and G-protein linked receptors and involving Ca2+ and ERK1/2. Detailed discussion are presented in the text. Abbreviations: PDGFR, platelet-derived growth factor receptor; EGFR, epidermal growth factor receptor; AngIIR, angiotensin II receptor; ET1R, endothelin 1 receptor; PLC, phospholipase; PIP2, phosphoinositol bisphosphate; IP3, inositol trisphos-phate; IP3R, inositol trisphosphate receptor; DAG, diacylgylcerol; PKC, protein kinase C; CAMKII, calcium/calmodulin dependent kinase II; MEK, mitogen activated/extracellular regulated kinase; ERK, extracellular signal regulated kinase; G, heterotrimeric G-protein; CADTK (also Pyk2), calcium dependent tyrosine kinase; PMCA, plasma membrane calcium ATPase; SERCA, sarco(endo)plasmic calcium ATPase; ßy, ßy sub-units of heterotrimeric G-proteins; ICRAC, putative capacitative entry channel.

the G1 phase triggering replication can be tightly controlled. The central components of signal transduction in ECs are (1) receptor linked tyrosine kinases (TKs), (2) phospholipase C (PLC), (3) the Ras-Raf-1 proteins, (4) phosphoinosi-tide hydrolysis: diacylglycerol and inositol trisphosphate generation, (5) the MAP kinase system, and (6) calcium mobilization. How these are interrelated is described in Figure 2.

Ultimately, these signal transduction cascades converge on the nucleus. The ordered sequence of events of the cell cycle is controlled by protein complexes composed of cyclin-dependent kinases (CDKs) and their catalytic part

Figure 3 Effect of an external sheath (stent) on neointima formation and vein graft thickening in a pig model. In these studies, a loose-fitting, that is, nonrestrictive, polyester sheath or stent (upper left panel) was placed around a saphenous vein into carotid artery interposition graft (upper right panel). After 1 month, the graft was excised and studied histologically. As can be seen (lower panel), there is a marked increase in graft size and neointima (NI) formation (the layer between the internal elastic lamina, IEL, and the lumen) compared to the original ungrafted saphenous vein (inset). The graft fitted with the external stent, however, shows a profound reduction of graft thickening (small arrow IEL and large arrow external elastic lamina, EEL) and a complete inhibition of neointima formation (see Figure 4 for higher magnification). This stented graft was characterized by profound microvessel growth (Figure 4). (see color insert)

Figure 3 Effect of an external sheath (stent) on neointima formation and vein graft thickening in a pig model. In these studies, a loose-fitting, that is, nonrestrictive, polyester sheath or stent (upper left panel) was placed around a saphenous vein into carotid artery interposition graft (upper right panel). After 1 month, the graft was excised and studied histologically. As can be seen (lower panel), there is a marked increase in graft size and neointima (NI) formation (the layer between the internal elastic lamina, IEL, and the lumen) compared to the original ungrafted saphenous vein (inset). The graft fitted with the external stent, however, shows a profound reduction of graft thickening (small arrow IEL and large arrow external elastic lamina, EEL) and a complete inhibition of neointima formation (see Figure 4 for higher magnification). This stented graft was characterized by profound microvessel growth (Figure 4). (see color insert)

ners, the cyclins. Cyclins bind to CDKs (designated cdc2 for the cell cycle), which then phosphorylate selected proteins. The Gj-phase specific D cyclins (D1rD2,D3) are key regulators in the transition of cells from quiescence to proliferation and progression through the Gj phase and the Gj/S transition. Cyclin D mRNAs are induced by growth factors, including vascular endothelial growth factor (VEGF), and are suppressed by antiproliferative agents. Induced overexpression of the D cyclins accelerates cell cycle progression and shortens the length of the cycle in many cell types.

A principal target for the cyclins in the control of cell cycle progression is the retinoblastoma (Rb) tumor suppressor gene Rb protein (Rbp), which suppresses mitosis. Phosphorylation of Rbp by the cyclin-CDK system negates its action, allowing replication to progress. Growth factors also elicit the rapid expression of proto-oncogenes, in particular c-fos and c-myc, which in turn are associated with the G0/Gj phase of the cell cycle. Another important intracellular mediator of VSMC proliferation is NFkB, which is classically activated in tissues subjected to inflammation.

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