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Chapter 15 Vascular Growth in Health and Disease 155

VEGF-A EphrinB2 DII4
PIGF VEGF-B VEGF-C VEGF-D Ang2 Ang1
PM

S=S

PM
Integrin
HSPG VE- NRP1
cadherin NRP2

VEGFR1 VEGFR2 VEGFR3 Tie1 Tie2 EphB4 Notch
Flt-1 KDR Flt-4
Flk-1

Angiogenesis Vessel maturation Branching
Lymphangiogenesis Arterial-venous identity

Angiogenic endothelium
SRC Motility
951
VEGFR2 P PI3K AKT Survival
VEGF-A eNOS Permeability
Shb P PLC
1175 PKC Gene expression
RAF
MEK MAPK Mitogenesis

Fig. 15.2 ELEMENTS OF THE SIGNALING CIRCUITRY INVOLVED IN BLOOD VESSEL FORMA-
TION AND TUMOR ANGIOGENESIS. Receptors and co-receptors involved in angiogenic, lymphangio-
genic, and regulatory signaling. Bottom panel: Outline of signaling pathways and their effector mechanisms
downstream of VEGF-A/VEGF. Dll4, Delta-like 4; eNOS, endothelial nitric oxide synthase; HSPG, heparan
sulfate proteoglycan; MAPK, mitogen-activated protein kinase; NRP, neuropilin; PI3K, phosphatidylinositol
3-kinase; PLC, phospholipase C; PlGF, Placental growth factor; PKC, protein kinase C; PM, plasma mem-
brane; VE-cadherin, vascular endothelial cadherin; VEGF, vascular endothelial growth factor; SRC, Rous
sarcoma virus-related proto-oncogene.

partially degraded collagens. Growth factors upregulate the expres- and VCAM1), all of which play distinct roles in the regulation of
sion of dimeric integrin receptors (αvβ3, αvβ5, α1β1, α2β1, α4β1, angiogenesis and vascular homeostasis. 2,5
α5β1), which recognize specific motifs in ECM molecules (often the
RGD sequence). Angiogenic growth factor receptors require integrin
interactions for their signaling function, while integrin αvβ3 is one of Proteases
several antiangiogenic targets under investigation. 2,4
Vascular endothelial cadherin (VE-cadherin/CD144) is selectively Proteases regulate remodeling, growth, and invasion of new blood
expressed by endothelial cells and contributes to their barrier func- vessels; liberation of ECM-bound angiogenic growth factors; genera-
tion, homotypic adhesion, and growth regulatory signals. Other tion of regulatory peptides (e.g., angiogenesis inhibitors); clotting and
cadherins, as well as claudins (e.g., endothelial claudin 5) and fibrinolysis; intracellular signaling; and numerous other steps involved
connexins, contribute to homo- and heterotypic endothelial cell in vascular maintenance and remodeling. For example, matrix
interactions, and the formation of gap and tight junctions, as well as metalloproteinases (MMPs) and their tissue inhibitors (TIMPs 1–4)
2
transmission of intercellular signals. On the other hand, interactions participate in the controlled ECM/basement membrane breakdown
between endothelium and circulating immune, myeloid, inflamma- that is required for invasiveness of the angiogenic endothelium. 2,18
tory, and progenitor cells, and platelets are mediated by selectins The key enzymes in this group include: MMP-1, MMP-2, MMP-9,
(e.g., P- L- and E-selectin), integrins (α4β1/VLA4), and members and MMP-14, coagulation factors (VIIa and thrombin) and their
of the immunoglobulin family of cell adhesion molecules (ICAM-1/2 receptors (tissue factor and PAR-1), plasminogen activators (uPA)