Vasculogenesis
angiopoietins (ang 1, 2, 3, 4)
involved in remodeling and maturation of the vascular system Angiopoietin-1: Activating Ligand for Tie-2 (receptor). Activates tyrosine kinase. Involved in maturation/survival of blood vessels, attracting ancillary cells (pericytes, smooth muscle cells). - quiescence Angiopoietin-2: Inactivating/antagonist ligand for Tie 2. Involved in positive and negative vascular remodeling . Ang-2 + VEGF = Vessel Sprouting growth Ang-2 - VEGF = Vessel regression/apoptosis
factors that initiate and influence vessel formation (in order)
hypoxia growth factors (upreg. due to hypoxia) proteases ECM and degradation products shear stress (occlusion, stenosis) stretch (muscle use)
clinically enhancing angiogenesis
important in diabetics, hypertension, where ability to respond to wound repair is diminished 1. bone marrow injections - to increase EPC count 2. increase VEGF - short-term therapy via gene therapy or injection of active protein unintended effects of exogenous VEGF - vascular permeability, edema, contraindicated to wound healing
progression of angiogenesis
initiating signal (ex: hypoxia) ECM proteolysis migration of endothelium into the matrix toward a signal proliferation of endothelial cells formation of blood vessel lumen, maturation of vessels increased permeability
insufficient vascularization
ischemic heart/limb disease placental insufficiency ulcers pulmonary/systemic hypertension vascular dementia lymphodema impaired wound healing (diabetes)
hypoxia
lower than normal oxygen concentration for the tissue sensitive cue that more blood flow is needed hypoxia inducible factor 1 alpha (HIF-1alpha) translocates to nucleus, upregulates production of VEGF and other GFs and proteins almost every mammalian cell is 50-100 microns from a capillary major cause of tumor vascularization and revascularization following ischemic events (stroke, MI, wound healing)
neuropilin-1
non-signaling VEGF receptor (coreceptor with VEGF receptor 2) potentiates the VEGF signal
heparan sulfate proteoglycans
non-signaling VEGF receptor, matrix sequestration
hemangioblast
precursor to endothelial and hematopoietic cells
VEGF receptor 1
receptor tyrosine kinase involved in motility (?)
VEGF receptor 2
receptor tyrosine kinase involved in proliferation
4 phases of vascular development
1. EC precursor, angioblast stage 2. primary capillary plexus formation 3. network expansion 4. vascular differentiation
vasculogenesis in the embryo
1. prior to vascularization, diffusion. 2. vasculogenesis first outside the embryo, in the yolk sac - vasculature derived from mesoderm 3. differentiation of pluripotent embryonic stem cells to HEMANGIOBLASTs via FGF and VEGF 4. hemangioblasts differentiate within BLOOD ISLANDS to angioblasts (precursors of endothelium) and hematopoietic cells (precursors to blood cells) 5. angioblasts - migrate, differentiate, assemble into solid endothelial cords forming a plexus with endocardial tubes 6. maturation of vessels 7. angiogenesis takes over, less angioblast involvement VEGF and VEGF-R1 and -R2 are critical for vascularization vessel maturation and progression are liked with angiopoietin and Tie-2
clinically inhibiting angiogenesis
EXTENSIVELY RESEARCHED! - inhibition of tumor growth by blocking blood supply 1. blocking VEGF signaling - remove VEGF activity (neutralizing antibody, soluble VEGF receptor to trap it), inhibit VEGF receptor signaling (chemically inhibit with tyrosine kinase inhibitor, block binding via antibody) 2. breakdown products of ECM molecules used as mimetics that directly interact with endothelium 3. Neovastat - natural MMP inhibitor
physiological blood vessel formation
LOTS of processes (organ development, wound healing, endurance training, etc.) very tightly controlled (uncontrolled growth = pathology)
proteolytic events
angiogenesis originates from capillary endothelia and post-capillary venules (not as much BM here!) vascular growth requires removal of matrix - performed by activated endothelium
FDA-approved anti-angiogenesis drugs
avastin (colorectal cancer) - neutralizing antibody to VEGF tarceva (lung cancer) - EGF tyrosine kinase inhibitor nexavar (renal cell carcinoma) - multiple tyr kin inhibitor sutent (advanced kidney cancer and GI stromal tumors) - multiple tyrosine kinase inhibitor
vasculogenesis
formation of blood vessels DE NOVO fetal development - from progenitor cells originating at distant sites (bone marrow, blood islands) adult - endothelial cell progenitors from bone marrow integrate into actively vascularizing sites
angiogenesis
formation, elongation and remodeling from EXISTING VASCULATURE due to local endothelial cell proliferation - cell division and sprouting normally, endothelia are quiescent cells recruitment of ancillary cells (pericytes/smooth muscle)
pathological blood vessel formation
tumor formation Kaposi's sarcoma (malignant epithelial cells) proliferative (diabetic) retinopathy age-related macular degeneration rheumatoid arthritis endometriosis psoriasis rosacea (adult acne) warts obesity
positive inducers from ECM breakdown
uPA (urokinase plasminogen activator) tPA (tissue plasminogen activator) MMPs (matrix metaloproteases) MtMMPs (membrane-type MMPs) matrix breakdown can release growth factors, creating chemotactic gradients
VEGF
vascular endothelial growth factor alternative splicing --> milti-isoforms 6 isoforms have different affinities for heparin (ECM protein) - affinity affects VEGF local diffusion rates - affects vessel leakiness, branching and diameter
heterogeneity within the vasculature
vasculature develops differently depending on type of vessel and microenvironment! artery/arteriole vein/venule capillary (microenvironment: liver (leaky) vs kidney (semi-permeable) vs brain (very tight)) surrounding/ancillary cell type (glial, SMC, pericyte) arborization (branching, unbranching via VEGF isotype)