Page 2079 - Hematology_ Basic Principles and Practice ( PDFDrive )

1848 Part XII Hemostasis and Thrombosis

an inductive pathway by upregulating VEGFR-2 in differentiating VEGF. 143,144 In the absence of growth factors, disruption of the vessel
mesoderm before vascular morphogenesis. 128–130 FGF2 may induce architecture by Ang2 may result in vascular cell apoptosis and vessel
neovascularization in adults indirectly through activation of the regression. However, Ang2-deficient mice are born alive, and the
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VEGF–VEGFR pathway. 131 major defect appears to be lymphatic development. Thus despite
major advances, the data are conflicting. The response of endothelial
Vascular Endothelial Growth Factors cells to the angiopoietins likely is context dependent and endothelial
Eight members of the VEGF family have been identified 86,126,128,132–137 : cell type specific. 144
VEGF-A (also called vascular permeability factor), VEGF-B, Tie1 is a receptor tyrosine kinase that exhibits structural similarities
VEGF-C, VEGF-D, VEGF-E (a viral ortholog), VEGF-F, VEGF-b, to Tie2. A ligand for Tie1 has not yet been identified. 126,147 Disruption
and placental growth factor. Three members of the receptor tyrosine of the Tie1 gene in mice results in lethality at a much later point in
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kinase family 126,135,136 —VEGFR-1 (flt-1), VEGFR-2 (flk-1/KDR), development; Tie1-null mice may survive up to birth. 145,148 Tie1 mice
and VEGFR-3 (flt-4)—respond differentially to individual members die of hemorrhage and edema, implicating Tie1 in signaling the control
of the VEGF family. In addition, the coreceptors for VEGF, neuro- of fluid exchange across capillaries and in maintenance of vessel integ-
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pilin 1 and neuropilin 2, have been identified on arterial and venous rity under hemodynamic stress. Chimeric mice that express Tie1 and
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+/−
endothelial cells, respectively. Neuropilin 1 is a coreceptor for Tie1 endothelial cells show underrepresentation of Tie1 cells in
VEGFR-2 that enhances binding of the VEGF-A isoform VEGF165 vessels primarily derived by angiogenesis but not in embryonic vessels
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to VEGFR-2. VEGF-A functions as a homodimer. However, it also derived by vasculogenesis, suggesting a differential function for Tie1 in
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heterodimerizes with VEGF-B and placental growth factor, and it has angiogenesis. Evidence also implicates a role for Tie1 in combination
a crucial dose-dependent effect on vasculogenesis. 86,126,128,135,136 with Ang1 in establishing vascular polarity. 150
Whereas VEGF-A binds VEGFR-1 and VEGFR-2, VEGF-C binds
VEGFR-2 and VEGFR-3. Whereas placental growth factor specifi- Platelet-Derived Growth Factors
cally activates VEGFR-1, VEGF-E binds only VEGFR-2. 128,135,136 The PDGF family is composed of four chains. PDGF-A and PDGF-B
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Lack of VEGFR-2 prevents the development of endothelial cells and can associate in a homodimeric or heterodimeric fashion. Similarly,
a hematopoietic system because cells lacking VEGFR-2 do not reach the receptors α and β are receptor tyrosine kinases that can form
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the correct location to form blood islands. Mice that have been homodimers or heterodimers. PDGF-BB can bind the receptors
rendered deficient for VEGFR-1 have normal hematopoietic progeni- PDGFR-ββ or PDGFR-αβ, but PDGFR-ββ binds only PDGF-BB
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tors and abundant endothelial cells, but they do not form capillary and not PDGF-AA or PDGF-AB. Mice that are null for PDGF-B
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tubes or functional vessels. Both VEGFR-2– and VEGFR-1–defi- die perinatally of renal, hematologic, and cardiovascular abnormali-
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cient mice die at an early embryonic stage, as do neuropilin 1– and ties. The large vessels and heart of these mice are dilated, and
neuropilin 2–deficient mice. In von Hippel-Lindau disease, develop- microvessels exhibit microaneurysms because of a lack of peri-
ment of hemangioblastomas may be caused by stabilization of VEGF cytes. 24,152 PDGFR-β knock-out mice do not show an overtly
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mRNA. VEGF is also believed to play a key role in propagating abnormal cardiovascular phenotype, but generation of chimeric mice
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tumor angiogenesis. Whereas tip cell migration has been shown to demonstrates that PDGFR-β cells are underrepresented in all
be dependent on a gradient of VEGF-A, endothelial proliferation in muscle lineages (smooth, cardiac, and skeletal). 153,154 Thus it appears
the lengthening vascular stalk is dependent on the absolute concen- that PDGF-BB elaborated by the endothelial cell provides a signal to
89
tration of VEGF-A, although both processes require VEGFR-2. recruit mesenchymal periendothelial cells as part of the maturation
Finally, injection of VEGF is capable of relieving limb ischemia by process of vascular morphogenesis. Two novel PDGF chains, PDGF-C
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155
the generation of collateral vessels. Whereas VEGF appears to col- and PDGF-D, have been identified. PDGF-CC can bind PDGFR-
laborate with the angiopoietins (Angs) to stimulate vascular develop- ββ or PDGFR-αβ, exhibits greater mitogenicity of mesenchymal
ment, VE-cadherin acts to temper the VEGF response. 33 cells than does PDGF-AA, and promotes wound repair. PDGF-DD
activates PDGFR-ββ and possibly PDGFR-αβ. PDGF-DD expres-
Angiopoietins sion has been found to be elevated in the serum of patients with
The Ang family of secreted glycoproteins comprises four members: various types of tumors and has been shown to have transforming
Ang1 to Ang4. All four bind to Tie2, a receptor tyrosine kinase. 141–144 and angiogenic activity. 155
Whereas Ang1 and Ang4 act as agonists of Tie2, Ang2 and Ang3
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function as antagonists of Tie2. However, the action of Ang2 is Transforming Growth Factors β
context dependent, and in some environments, it may behave as an Members of the transforming growth factor-β (TGFβ) family are
144
agonist. Binding of Ang1 to Tie2 results in tyrosine phosphoryla- multifunctional homodimeric peptides with diverse effects on cell
tion of Tie2 and promotes endothelial cell survival but not prolifera- proliferation, migration, differentiation, adhesion, and expression of
tion. 141,144 Early in development, Ang1 is found mainly in the cell adhesion molecules and ECM. 126,156,157 They are secreted as inac-
myocardium surrounding the endocardium, but it also becomes tive precursors. After being activated, they transmit signals to cells by
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expressed in the mesenchyme surrounding developing vessels. binding heteromeric complexes of type I and type II serine/threonine
Disruption of either Ang1 or its receptor Tie2 in the mouse results kinase receptors. In most cell types, the type I receptor engaged by
in embryonic lethality because of similar defects. 142,145 These mice die TGFβ is activin receptor-like kinase 5 (ALK5). However, in endothe-
158
at a slightly later stage than do VEGFR-deficient mice. Although lial cells, TGFβ can bind and signal through ALK5 and ALK1.
endothelial cells are present, they have a lack of vascular complexity Contact between endothelial cells and periendothelial cells is required
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and a scarcity of periendothelial cells. Reciprocal interactions between for production of active TGFβ. Mice lacking TGFβ or TGFβ recep-
the endothelial cells and surrounding matrix and mesenchyme appear tor type II exhibit similar defects in vasculogenesis and hematopoie-
to be disrupted. An activating Tie2 mutation in humans causes vas- sis. 156,157 Endothelial proliferation is not affected, but poor contacts
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cular malformations that show a disproportionate number of endo- between endothelial cell and mesothelial layers in embryos of TGFβ
thelial cells compared with smooth muscle cells, resulting in dilated, mice result in a disorganized and reduced vascular network lacking
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tortuous vascular channels in certain tissues. Mice engineered to capillary tubes. Mutations in two TGFβ receptors, ALK1 and the
overexpress Ang2 specifically in their vasculature show embryonic accessory TGFβ receptor endoglin, have been linked to the vascular
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lethality and vascular defects that are reminiscent of those seen in disorder hereditary hemorrhagic telangiectasia. Disruption of TGFβ
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Ang1- or Tie2-null embryos. In one proposed model, Ang1–Tie2 signaling likely plays a role in the telangiectasia seen in this disorder.
coupling mediates vascular maturation by sustaining endothelial
cell–periendothelial cell–matrix interactions and may be involved in Notch
maintaining endothelial cell quiescence. Because Ang2 is found only The Notch family is composed of four receptors (Notch1 through
at sites of vascular remodeling, Ang2 loosens matrix contacts, thus Notch4) and five ligands (Jagged1 and Jagged2 and Delta-like 1
allowing access and responsiveness to angiogenic factors such as [Dll1], Dll3, and Dll4). Ligand engagement results in a series of