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154 Part II Cellular Basis of Hematology

TABLE Molecular Regulators of Vascular Growth and Remodeling
15.1
Regulator Main Receptor(s) Biologic Activity
Angiogenic Effectors Central to Endothelial and Mural Cell Function
VEGF-A/VEGF VEGFR2 (VEGFR3, VEGF1), NRP1 Stimulator of angiogenic functions, migration and survival of ECs,
including formation of tip cells
VEGF-C VEGFR3 (VEGFR2) Stimulator of angiogenesis (ECs) and lymphangiogenesis (LECs)
Ang 1 Tie2 Positive regulator of endothelial–mural interactions, EC survival, and
vessel maturation
Ang 2 Tie2 Negative regulation of endothelial–mural interactions, stimulator of
lymphangiogenesis
Dll4 Notch Inhibitor of tip cell formation
Jag1 Notch Stimulator of tip cell formation
EphrinB2 EPHB4 VEGFR internalization/signaling, arterial identity, tube formation
PDGF-B PDGFRβ Recruitment of mural cells, vessel maturation
TGFβ1 TGFβRII Differentiation of mural cells, ECM formation
Integrins (αv, β1, β5) ECM proteins EC survival, migration morphogenesis
Stimulators Involved in Pathologic Angiogenesis
PlGF VEGFR1 Stimulates angiogenesis by interaction with ECs and BMDCs
Acidic FGF (FGF-1) FGFRs 1–4 Stimulator of EC mitogenesis, survival, and angiogenesis
Basic FGF (FGF-2) FGFRs 1–4 Stimulator of EC mitogenesis, survival, and angiogenesis
FGF-3 FGFRs 1–4 Stimulator of EC mitogenesis, survival, and angiogenesis
FGF-4 FGFRs 1–4 Stimulator of EC mitogenesis, survival, and angiogenesis
IL-8 CXCR1 Stimulator of ECs and inflammatory cells
IL-6 IL-6R Stimulator of inflammatory angiogenesis
TNFα TNFR1 (p55) EC stimulator and VEGF inducer
Bv8 GPCR Stimulator of endocrine and tumor ECs
PD-ECGF/TP Unclear Stimulator of angiogenesis
Angiogenin 170-kDa receptor Stimulator of angiogenesis and tRNAse
MMP9 ECM proteins Matrix metalloproteinase that breaks down the ECM and releases
angiogenic growth factors
Endogenous Angiogenesis Inhibitors
Inhibitor Biologic Activity
TSP-1 Interacts with the CD36 receptor, integrins, and other proteins, causing growth inhibition and apoptosis of
angiogenic ECs
Endostatin Proteolytic fragment of collagen XVIII with antiangiogenic activity
Angiostatin Proteolytic fragment of plasminogen with antiangiogenic activity
Tumstatin Proteolytic fragment of collagen IV alpha 3 chain
sFlt-1/sVEGFR1 Soluble splice variant of VEGFR1 neutralizing VEGF and blocking VEGFR2 signaling
VEGF165b Splice variants of VEGF with antiangiogenic activity
PEX Inhibitor of EC invasion and MMP activity
IFNα (β) Inhibits release of angiogenic growth factors
Ang (1,2), Angiopoietin; Bv8, Bombina variegata protein; Dll4, delta-like 4; FGF, fibroblast growth factor; GPCR, G-protein-coupled receptor; IFN, interferon; IL-6,
interleukin 6; IL-8, interleukin 8; Jag1, Jagged 1; MMP9, matrix metalloproteinase 9; PD-ECGF/TP, platelet-derived endothelial cell growth factor/thymidine
phosphorylase; PDGF, platelet-derived growth factor; PlGF, placenta growth factor; TNFα, tumor necrosis factor alpha; TSP-1, thrombospondin 1; VEGF, vascular
endothelial growth factor. See text and references for details. 2

5
(sprouts), as depicted in Figs. 15.2 and 5.3. Dll1 is also involved Other ephrins are implicated in endothelial–pericyte interactions,
in circumferential vascular enlargement (arteriogenesis; Fig. 15.4). 2 and communication between blood vessels and tumor cells. They
may also cooperate in VEGFR2 endocytosis and signaling. 2
Ephrins and Eph Receptors
Vascular Integrins, Cadherins, and Cell
The arterial or venous identity of endothelial cells in the evolving Adhesion Molecules
microcirculation is preprogrammed by the expression of transmem-
brane guidance molecules, especially ephrin B2 and its EPHB4 recep- Quiescent endothelial cells are anchored to the basement membrane, a
tor. Bidirectional signals emanating from these molecules, together structured layer of ECM composed mainly of laminin and collagen type
with mechanosensory cues, govern the arteriovenous vascular arbo- IV. In contrast, growing (angiogenic) endothelial cells are surrounded
rization that is essential for, and maintained by, proper blood flow. by provisional ECM containing fibrin, vitronectin, fibronectin, and