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VEGF-B VEGF-B Also Called VEGF-Related Factor/VRF

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VEGF-B VEGF-B Also Called VEGF-Related Factor/VRF Diversity of angiogenic factors lecture VII 20th April 2015 Diversity of angiogenic factors/receptors Ang1 + ephrins Ang2 - IgG superfamily VEGF (VCAM-1, ICAM-1) Ang3 - B1 A1 B2 A B C D E PlGF + Ang4 ? B2 B3 B4 A2 ephrin receptors Integrins E, P selectin VEGFR-1 VEGFR-2 TIE-2 TIE-1 sVEGFR NRP-1 VEGFR-3 Jain and Munn Nature Med. 2000, modified VEGF family • three types of ligands • the ligands are further diversified by alternative splicing Shortly about VEGF-A Isoform Size Coding exons Features (amino acid) VEGF-A121 121 1-5, 8 Secreted VEGF-A145 145 1-6, 8 Binds NRP2 but not NRP1; secreted VEGF-A165 165 1-5, 7, 8 The most abundant and biologically active isoform; secreted; binds NRP1 and NRP2 VEGF-A165b 165 1-5, 7, alternative exon 8 Secreted, endogenous inhibitory form of VEGF-A165 VEGF-A183 183 1-5, short exon 6, 7, 8 Sequestered in ECM but released by cleavage VEGF-A189 189 1-8 Sequestered in ECM but released by cleavage VEGF-A206 206 1-8 plus additional exon Sequestered in ECM but released by cleavage - a ligand for VEGFR-1, VEGFR-2 - a potent pro-survival, pro-migratory and pro-proliferative agent VEGF family VEGF-B VEGF-B also called VEGF-related factor/VRF - VEGF-B was discovered in 1996 as a VEGF-A homolog - a ligand for VEGFR-1 - two isoforms: VEGF-B167 (binds to heparan sulfate) and VEGF-B186 - VEGF-B167 is nonglycosylated, predominant form, representing up to 90% of the transcripts in adult mouse tissues - it might modulate VEGF-A signaling by forming heterodimers with VEGF-A and was found to be coexpressed with it in heart and skeletal muscle and other tissues VEGF-B is a close relative to VEGF-A Li et al., Trends Mol Med. 2012 VEGF-B exists in two different spilicing forms Li et al., Trends Mol Med. 2012 Heparin –binding domain unique VEGFB186 domain Silk domain Li & Eriksson, 2001 Through alternative splicing the human PlGF, VEGF, and VEGF-B genes can encode multiple different protein isoforms. VEGF-B knockout The VEGF-B knockout mice are viable and fertile with no obvious morphological changes, suggesting that VEGF-B does not play a major role in vascular development. VegfB-knockout mice have small hearts and atrial conduction defects but both cardiac and retinal blood vessels develop normally in these animals Li et al., Trends Mol Med. 2012 VEGF-B also called VEGF-related factor/VRF • may contribute to the embryonic myocardial vascularization • it is expressed early during fetal development and is widely distributed, being prominently expressed in the cardiac myocytes, in skeletal muscle and smooth muscle cells of large vessels VEGF-B • VEGF-B is also expressed in the nervous system, especially in the cerebral cortex • may play a role in pathological angiogenesis • recent evidence indicate that it is also expressed in tumor tissues, as its elevated level has been detected in breast carcinoma, melanoma and fibrosarcoma as well as in a variety of cultured tumor cell lines VEGF-B does not induce vessel permeability Brkovic et al., J Cell Biochem. 2007 Pro-angiogenic effects of VEGF-B under pathological conditions In a laser injury-induced choroidal neovascularization model and an ischemia-induced retinal neovascularization model, subretinal injection of AAV- VEGF-B167 or AAV-VEGF-B186 augmented neovessel formation in the retinae and choroids VEGF-B is most abundantly expressed in the heart and is important for cardiac blood vessel survival. In a cardiac ischemia mouse model, VEGF-B treatment increased cardiac blood vessel density in the ischemic myocardium, where blood vessels underwent severe degeneration Li et al., Trends Mol Med. 2012 VEGF-B is a potent survival factor for different types of neurons - In vitro, VEGF-B protein treatment increased the survival of cultured primary brain cortical neurons and protected cultured primary motor neurons from apoptosis - In vivo, VEGF-B treatment reduced stroke volume in a middle cerebral artery ligation- induced stroke model - In the retina, VEGF-B treatment increased the survival of retinal ganglion cells in an optic nerve crush injury model and protected neurons in different nuclear layer in the retina in an NMDA-induced neuronal apoptosis model - Loss-of-function assays showed that Vegf-b deficiency in mice led to more severe strokes in the experimental stroke model and exacerbated retinal ganglion cell death in the optic nerve crush injury model NEUROPROTECTIVE EFFECTS OF VEGF-B Increased Severity of Cerebral Ischemic Injury in VEGF-B-Deficient Mice Infarct volume is increased after middle cerebral artery occlusion (MCAO) in VEGF-B knockout mice- potential neuroprotective effect of VEGF-B VEGF-B protects the brain from ischemia Sun Y. et al. JCBFM, 2004 VEGF family –VEGF-C VEGF family VEGF-C - like VEGF, stimulates the migration of EC and increases vascular permeability and EC proliferation (but at higher concentrations than VEGF) Brkovic et al., J Cell Biochem. 2007 - binds to VEGFR-3 (FLT4) and VEGFR-2; binds also to Nrp-2 - regulates physiological and pathological blood vessel growth in vivo VEGF-C • regulates growth of lymphatic vessels • overexpression of VEGF-C in skin keratinocytes leads to dermal-lymphatic vessel hyperplasia • VEGF-C- knockouts – results in defects in intestinal and cutaneous lymphatic vessels Lymphatic system Gasparo Assellius – 1627 Functions: Lymphatic vessels 1. The main purpose of lymphatic vessels is to absorb and return lymph fluid from the body back to the blood 2. Immune functions 3. Role in pathology: • lymphaedema (insuficient) • tumor growth and metastatis (overgrowth of lymphatic vessels) Blood and lymphatic vessels Similarly to the blood vessels lymphatic vessels are lined by the endothelium, The endothelium has fewer tight junctions than that of blood vessels and could be porous so this is probably the cause of the greater permeability of the lymphatic vessels. The lymphatics are a low flow and a low- pressure system - their walls are thinner and consequently lumens are wider (about three fold) than those of blood capillaries and they are more irregularly shaped Lymphatic capillaries are deficient in mural cells and are characterized by an incomplete or absent basement membrane. Jones N et al, RevMolCellBiol. 2001 Vessels – blood vs lymphatic Blood vessel Lymphatic capillaries capillaries Endothelial Abundant Scant cytoplasm cells cytoplasm Cell–cell Loose, valve-like junctions Adherens, tight overlaps Basement Present Mostly absent membrane Pericytes Present None Blood Present Usually absent Schmid-Schonbein, Physiol. Rev. (1990); Nathanson et al., Cancer (2003) Gnepp and Green, Scan. Electron Microsc. (1979) Lymphatic vessels In the past, lymphatic vessels were defined largely by the lack of erythrocytes in their lumen, a lack of junctional complexes and the lack of a well-defined basement membrane. Now, lymphatic-specific vascular endothelial growth factors (VEGF-C and VEGF-D) and molecular cell surface markers such as the VEGFR-3, podoplanin, Prox-1, LYVE-1 have been identified. Podoplanin Prox1 LECs – lymphatic endothelial cells Lyve1 VEGFR 3 (Flt4) Lymphatic vessel endothelial hyaluronian receptor 1 Body Fluid Volume Homeostasis Lymphedema Lymphedema... is an accumulation of fluid containing excessive proteins in the interstitium caused by impairment of lymph vessels resulting in chronic inflammation fibrosis adipose degeneration poor immune function impaired wound healing Lymphedema is a condition of localized fluid retention and tissue swelling caused by a damaged lymphatic system Lymphedema may be inherited (primary) or caused by injury to the lymphatic vessels (secondary). It is most frequently seen after lymph node dissection, surgery and/or radiation therapy, in which damage to the lymphatic system is caused during the treatment of cancer, most notably breast cancer Primary congenital lymphedema (Milroy disease) is a rare autosomal dominant condition. Molecular results Most patients had mutations within one of the two kinase domains of VEGFR-3. http://www.lymphadvice.com http://www.laurantis.com VEGF-C/D Li et al., Trends Mol Med. 2012 VEGF homology domain Heparin –binding domain unique VEGFB186 domain N-terminal pro-peptide domain Silk domain (contains C-terminal pro-peptide domain) Li &Eriksson, 2001 Processing of VEGF-C Proteolytic activations of VEGFs binding activity of processed VEGF-D to VEGFR-2 increases by 290-fold McColl et al., APMIS 2004 VEGF-D c-FOS induced growth factor (FIGF) - 61% of aa identity to VEGF-C - binds VEGFR-3 and VEGFR-2 - also proteolytically processed in a similar way like VEGF-C - stimulates EC proliferation - is lymphangiogenic when overexpressed in skin keratinocytes VEGF-C and VEGF-D signaling VEGF-C and VEGF-D signaling Karkkainen et al., Nature Cell Biol 2002 Blood and lymphatic vascular effects of various VEGFs in the mouse skin LYVE-1, red PECAM-1/CD31, green Tammela et al. Cardiovasc Res 2005 VEGFR-3 Present on all endothelia during development, but in the adult becomes restricted to lymphatic EC and certain fenestrated blood vascular EC. Up-regulated on blood vascular EC in tumors Functions of VEGF-C and VEGF-D in tumors - produced by tumor and stromal cells - signal through VEGFR-2 – leads to angiogenesis and tumor growth - signal through VEGFR-3 - on lymphatic endothelial cells – promotes metastasis - modulate also immune functions: VEGF-C – is chemotactic for macrophages – express VEGFR-3, macrophages also express and secrete VEGF-C and VEGF-D Role of VEGF-C and D in angiogenesis and lymphangiogenesis VEGF-D VEGF family VEGF family Placental growth factor - expressed
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