Page 201 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 15 Vascular Growth in Health and Disease 153

Bone marrow–derived cells Resident vascular cells Cancer cells

Endothelial cells (CD31 , CD144 )
Mural cells — pericytes

Endothelial progenitor cells (aSMA , NG2 ) Tumor-initiating cells

(VEGFR2 , CD45 , CD133 ) (CD133 , markers of

endothelial cells or
pericytes)
Neutrophils and myeloid Angiogenesis Macrophages

suppressors (Gr1 , CD11b)
(CD11b , F4/80)

Vascular Tie-2 expressing Platelets Hemangiocytes Myeloid cells

leukocytes monocytes (TEMs) (CD41 ) (VEGFR1 , (VEGFR1 , CXCR4 ,

(CD11b , CD144 ) (CD11b , Tie-2 ) CXCR4 ) CD11b )

Fig. 15.1 CELL POPULATIONS INVOLVED IN VASCULAR GROWTH AND TUMOR ANGIOGEN-
ESIS. Cells involved in blood vessel formation include endothelial cells, their progenitor cells, mural cells
(pericytes), several populations of bone marrow–derived cells, as well as angiogenic fibroblasts, platelets, cancer
2
4
cells, stem cells, and immune effectors not included in this diagram (based on Carmeliet and Jain , Kerbel ,
13
and De Palma and Naldini ). VEGFR, Vascular endothelial growth factor receptor.
Vascular Endothelial Growth Factors homo- or heterodimers of which interact preferentially with one
of the three known cellular RTKs, namely PDGFRα, PDGFRβ,
Vascular endothelial growth factor-A (VEGF-A), which is also known as and PDGFRγ, each endowed with different cellular functions. For
VEGF or vascular permeability factor (VPF), is indispensable for vascular example, PDGF-BB is expressed by endothelial cells and mediates
development. 2,3,5 VEGF is the key member of a larger family of related their capacity to attract mural cells harboring PDGFRβ. 2
polypeptides, which includes VEGF-B, VEGF-C, VEGF-D, VEGF-E,
2
VEGFR-F, and placental growth factor (PlGF). Upon dimerization,
these factors bind to their tyrosine kinase receptors (RTKs/VEGFRs), Prokineticins
including VEGFR1/Flt-1, VEGFR2/KDR/Flk-1, and VEGFR3/Flt-4,
2
often in conjunction with their neuropilin coreceptors (NRP1, NRP2), This group of factors consists of the endocrine gland vascular
as depicted in Fig. 15.2. For instance, VEGF-A interacts with VEGFR2, endothelial growth factor/prokineticin 1 (EG-VEGF/PK1) and the
VEGFR1, and VEGFR3, while PlGF is selective for VEGFR1. The protein 8/prokineticin 2 (Bv8/PK2) secreted by Bombina variegata,
distribution of different VEGFRs on vascular (VECs) and lymphatic both of which interact with their respective G-protein–coupled
(LECs) endothelial cell subsets, as well as among EPCs, hematopoietic, receptors on endothelial cells (PK-R1 and PK-R2). These mediators
myeloid, and certain tumor cells, defines the known biologic activities induce VEGF-like effects in endothelial cells and may render tumors
of various VEGF ligands. The effects of VEGF include stimulation resistant to VEGF inhibition. 5
of endothelial mitogenesis, migration, survival, morphogenesis, and
vascular permeability (e.g., through formation of intercellular gaps
3
or transcellular structures know as fenestrae). The signaling activity Angiopoietins and Tie Receptors
of VEGFR2 is crucial for these processes, whereas VEGFR1 is often
expressed as a soluble splice variant (sFlt-1) that neutralizes VEGF (acts Angiopoietins (Ang1, 2, and 4) interact with the Tie2/TEK receptor
as VEGF “sink”), thereby inhibiting angiogenesis. 2 (RTK), which is preferentially expressed by endothelial cells and
VEGF activity is also regulated by splicing of the corresponding some myeloid cells (see Figs. 15.1 and 15.2). A related orphan recep-
mRNA, which results in the generation of several protein isoforms, tor, known as Tie1, remains poorly characterized and likely acts by
2
including VEGF121, VEGF145, VEGF165, VEGF189, and modulating Tie2 activity. Ang1 emanates from perivascular tissues
2,5
VEGF206 (designations based on the number of amino acids). and serves as the main Tie2 agonist to stabilize endothelial–mural
These variants differ in their cell association, solubility, and their cell interactions and to promote endothelial cell survival, vascular
ability to bind heparinoids or to interact with neuropilins, all of quiescence, and the nonpermeable state. Ang2, which is produced
which define the formation of extracellular gradients and related by VEGF-stimulated endothelium, exerts the opposite effect and
biologic responses. In this regard, VEGF165 is an especially potent stimulates pericyte detachment, permeability, vascular growth, or
inducer of angiogenesis (Fig. 15.3). VEGF-C and VEGF-D stimu- regression, as well as lymphangiogenesis. 2
late the growth of lymphatics (lymphangiogenesis) via activation of
VEGFR3, while VEGF-B and PlGF interact with VEGFR1 and are
involved in vascular pathologies and inflammation. 2 Notch Pathway
Delta-like (Dll1, 3 and 4) and Jagged (1 and 2) are membrane-bound
Platelet-Derived Growth Factors ligands that activate Notch receptors (Notch 1–4) on adjacent cells.
During vascular development and growth Dll4 and Jagged 1 are
This family of VEGF-related growth factors consists of four expressed by subsets of endothelial and mural cells, respectively,
members: PDGF-A, PDGF-B, PDGF-C, and PDGF-D, the and regulate their distinct functions within the capillary outgrowths