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Angiogenesis and the neurovascular link
Vascular Pharmacology 56 (2012) 306–344
Contents lists available at ScienceDirect
Vascular Pharmacology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / v p h
EMVBM 2011 Lectures and Oral☆ OPENING LECTURE PL.1 Discovery of the defensive system of endothelium Andrzej Szczeklik Department of Medicine, Jagiellonian University Medical College, 31-066 Krakow, ul. Skawinska, Poland E-mail address: [email protected] Rudolf Virchow, who in 1860 observed endothelium at autopsy, called it “a membrane”. In 1994 Sir John Vane called endothelium “a maestro of blood circulation”. This radical change of perspective was due to the major discoveries that took place in the last quarter of the 20th century. We know now that the endothelium is the main defensive barrier in the cardiovascular system. It achieves this goal by synthesizing several chemical compounds with powerful biological activity, of which prostacyclin and nitric oxide are most important. Other compounds, like heme oxygenase-1, are also emerging. The history of these discoveries, which opened new avenues in cardiology, gives us glimpses of brilliant human minds at work, and also teaches us that in scientific experiments we should never ignore the unexpected. doi:10.1016/j.vph.2011.08.004
PLENARY SESSION 1 Mechanisms of blood vessel formation PL.1.1 Angiogenesis and the neurovascular link Peter Carmeliet Laboratory of Angiogenesis & Neurovascular Link, Vesalius Research Center (VRC), VIB, K.U. Leuven, B-3000 Leuven, Belgium E-mail address: [email protected] Understanding the molecular basis of the formation of blood vessels (angiogenesis) and nerves (neurogenesis) is of great medical relevance. It is well known that dysregulation of angiogenesis leads to tissue ischemia, cancer, inflammation and other disorders, while a dysfunction of the nerve system contributes to motorneuron disorders like amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. The observations of Andreas Vesalius – Belgian anatomist of the 16th century – that patterning of vessels and nerves shows more than remarkable similarities, are currently revisited in exciting studies. This neuro-vascular link not only is critical for ☆ This issue of Vascular Pharmacology contains abstracts as supplied by the authors. Only typographical errors may have been corrected.
development, but also, when deregulated, contributes to the pathogenesis of medically relevant diseases. Studying the molecular nature of this link thus promises to accelerate the discovery of new pathogenetic insights and therapeutic strategies for the treatment of both vascular and neurological diseases. doi:10.1016/j.vph.2011.08.005
PL.1.2 Growth factors and inhibitors of tumor angiogenesis and lymphatic metastasis Kari Alitalo and Collaborators Molecular/Cancer Biology Laboratory, Haartman Institute and Finnish Institute for Molecular Medicine, Biomedicum Helsinki, P.O.B. 63, 00014 University of Helsinki, Finland E-mail address: [email protected] Vascular endothelial growth factor (VEGF) stimulates angiogenesis and permeability of blood vessels via its two receptors VEGFR-1 and VEGFR-2, but it has only little lymphangiogenic activity. The third receptor, VEGFR-3, does not bind VEGF and its expression becomes restricted mainly to lymphatic endothelia during development. Homozygous VEGFR-3 targeted mice die around midgestation due to failure of cardiovascular development, whereas transgenic mice expressing the VEGFR-3 ligand VEGF-C or VEGF-D show evidence of lymphangiogenesis and VEGF-C knockout mice have defective lymphatic vessels. The proteolytically processed form of VEGF-C binds also to VEGFR-2, as we have recently shown in crystal structure analysis, and is angiogenic and in vivo. Proteolytic processing also generates a form of VEGF-D that is only angiogenic. Thus VEGF-C and VEGF-D appear to provide both angiogenic and lymphangiogenic activities. VEGF-C overexpression induces lymphangiogenesis and growth of the draining lymphatic vessels, intralymphatic tumor growth, lymph node lymphangiogenesis and metastasis. The Notch pathway and the PDZ domain protein CLP24 that interacts with the VEGFR-2 and VEGFR-3 pathways were also shown to regulate lymphatic vessel growth and development. Furthermore, soluble VEGFR-3 and antibodies blocking VEGFR-3 inhibited embryonic and tumor lymphangiogenesis and lymphatic metastasis. These results have indicated that paracrine signal transduction between tumor cells and the lymphatic endothelium is involved in lymphatic metastasis. We have recently found a role for VEGFR-3 signaling also in settings of physiological and pathological angiogenesis. Enhanced VEGFR-3 expression was detected in endothelial sprouts, and blocking of VEGFR-3 signaling inhibited angiogenic sprouting. Blocking of the Notch signaling pathway lead to widespread endothelial VEGFR-3 expression and excessive angiogenesis, which was inhibited by blocking VEGFR-3. VEGF-C and VEGFR-3 blocking antibodies provided significant inhibition of tumor angiogenesis and growth and in mouse they improved tumor growth inhibition by anti-VEGFR-2 therapy in mouse
Contents lists available at ScienceDirect
Vascular Pharmacology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / v p h
EMVBM 2011 Lectures and Oral☆ OPENING LECTURE PL.1 Discovery of the defensive system of endothelium Andrzej Szczeklik Department of Medicine, Jagiellonian University Medical College, 31-066 Krakow, ul. Skawinska, Poland E-mail address: [email protected] Rudolf Virchow, who in 1860 observed endothelium at autopsy, called it “a membrane”. In 1994 Sir John Vane called endothelium “a maestro of blood circulation”. This radical change of perspective was due to the major discoveries that took place in the last quarter of the 20th century. We know now that the endothelium is the main defensive barrier in the cardiovascular system. It achieves this goal by synthesizing several chemical compounds with powerful biological activity, of which prostacyclin and nitric oxide are most important. Other compounds, like heme oxygenase-1, are also emerging. The history of these discoveries, which opened new avenues in cardiology, gives us glimpses of brilliant human minds at work, and also teaches us that in scientific experiments we should never ignore the unexpected. doi:10.1016/j.vph.2011.08.004
PLENARY SESSION 1 Mechanisms of blood vessel formation PL.1.1 Angiogenesis and the neurovascular link Peter Carmeliet Laboratory of Angiogenesis & Neurovascular Link, Vesalius Research Center (VRC), VIB, K.U. Leuven, B-3000 Leuven, Belgium E-mail address: [email protected] Understanding the molecular basis of the formation of blood vessels (angiogenesis) and nerves (neurogenesis) is of great medical relevance. It is well known that dysregulation of angiogenesis leads to tissue ischemia, cancer, inflammation and other disorders, while a dysfunction of the nerve system contributes to motorneuron disorders like amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. The observations of Andreas Vesalius – Belgian anatomist of the 16th century – that patterning of vessels and nerves shows more than remarkable similarities, are currently revisited in exciting studies. This neuro-vascular link not only is critical for ☆ This issue of Vascular Pharmacology contains abstracts as supplied by the authors. Only typographical errors may have been corrected.
development, but also, when deregulated, contributes to the pathogenesis of medically relevant diseases. Studying the molecular nature of this link thus promises to accelerate the discovery of new pathogenetic insights and therapeutic strategies for the treatment of both vascular and neurological diseases. doi:10.1016/j.vph.2011.08.005
PL.1.2 Growth factors and inhibitors of tumor angiogenesis and lymphatic metastasis Kari Alitalo and Collaborators Molecular/Cancer Biology Laboratory, Haartman Institute and Finnish Institute for Molecular Medicine, Biomedicum Helsinki, P.O.B. 63, 00014 University of Helsinki, Finland E-mail address: [email protected] Vascular endothelial growth factor (VEGF) stimulates angiogenesis and permeability of blood vessels via its two receptors VEGFR-1 and VEGFR-2, but it has only little lymphangiogenic activity. The third receptor, VEGFR-3, does not bind VEGF and its expression becomes restricted mainly to lymphatic endothelia during development. Homozygous VEGFR-3 targeted mice die around midgestation due to failure of cardiovascular development, whereas transgenic mice expressing the VEGFR-3 ligand VEGF-C or VEGF-D show evidence of lymphangiogenesis and VEGF-C knockout mice have defective lymphatic vessels. The proteolytically processed form of VEGF-C binds also to VEGFR-2, as we have recently shown in crystal structure analysis, and is angiogenic and in vivo. Proteolytic processing also generates a form of VEGF-D that is only angiogenic. Thus VEGF-C and VEGF-D appear to provide both angiogenic and lymphangiogenic activities. VEGF-C overexpression induces lymphangiogenesis and growth of the draining lymphatic vessels, intralymphatic tumor growth, lymph node lymphangiogenesis and metastasis. The Notch pathway and the PDZ domain protein CLP24 that interacts with the VEGFR-2 and VEGFR-3 pathways were also shown to regulate lymphatic vessel growth and development. Furthermore, soluble VEGFR-3 and antibodies blocking VEGFR-3 inhibited embryonic and tumor lymphangiogenesis and lymphatic metastasis. These results have indicated that paracrine signal transduction between tumor cells and the lymphatic endothelium is involved in lymphatic metastasis. We have recently found a role for VEGFR-3 signaling also in settings of physiological and pathological angiogenesis. Enhanced VEGFR-3 expression was detected in endothelial sprouts, and blocking of VEGFR-3 signaling inhibited angiogenic sprouting. Blocking of the Notch signaling pathway lead to widespread endothelial VEGFR-3 expression and excessive angiogenesis, which was inhibited by blocking VEGFR-3. VEGF-C and VEGFR-3 blocking antibodies provided significant inhibition of tumor angiogenesis and growth and in mouse they improved tumor growth inhibition by anti-VEGFR-2 therapy in mouse