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)