BACKGROUND EGFR and VEGFR2 protein expressions are hallmarks of clear cell renal cancer (RCC) with questionable prognostic impact. The skeletal system is one of the most common metastatic sites of RCC. Unfortunately, there are no data for EGFR and VEGFR2 protein expression in such lesions. MATERIALS AND METHODS Twenty cases of bone metastatic clear cell RCC were analyzed. EGFR and VEGFR2 prot...

The specific role of VEGFA-induced permeability and vascular leakage in physiology and pathology has remained unclear. Here we show that VEGFA-induced vascular leakage depends on signalling initiated via the VEGFR2 phosphosite Y949, regulating dynamic c-Src and VE-cadherin phosphorylation. Abolished Y949 signalling in the mouse mutant Vegfr2(Y949F/Y949F) leads to VEGFA-resistant endothelial adh...

The vascular endothelial growth factor (VEGF) signaling pathway has been implicated in tumor angiogenesis, and inhibition of the VEGF pathway is considered an efficacious method for treating cancer. Herein, we describe synthetic studies of imidazo[1,2-b]pyridazine derivatives as VEGF receptor 2 (VEGFR2) kinase inhibitors. The imidazo[1,2-b]pyridazine scaffold was designed and synthesized as a h...

Neuropilin 1 (NRP1) plays an important but ill-defined role in VEGF-A signaling and vascular morphogenesis. We show that mice with a knockin mutation that ablates the NRP1 cytoplasmic tail (Nrp1(cyto)) have normal angiogenesis but impaired developmental and adult arteriogenesis. The arteriogenic defect was traced to the absence of a PDZ-dependent interaction between NRP1 and VEGF receptor 2 (VE...

The bone morphogenic protein antagonist gremlin is expressed during embryonic development and under different pathologic conditions, including cancer. Gremlin is a proangiogenic protein belonging to the cystine-knot superfamily that includes transforming growth factor-β proteins and the angiogenic vascular endothelial growth factors (VEGFs). Here, we demonstrate that gremlin binds VEGF receptor...

For the purpose of discovering novel type-II inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2) kinase, we designed and synthesized 5,6-fused heterocyclic compounds bearing a anilide group. A co-crystal structure analysis of imidazo[1,2-b]pyridazine derivative 2 with VEGFR2 revealed that the N1-nitrogen of imidazo[1,2-b]pyridazine core interacts with the backbone NH group of C...

Syntenin, a tandem PDZ-domain-containing scaffold protein, is involved in the regulation of diverse biological functions, including protein trafficking, exosome biogenesis, and cancer metastasis. Here, we present the first study to explore the significance of syntenin in endothelial cells. Syntenin knockdown in human umbilical vein endothelial cells (HUVECs) impaired vascular endothelial growth...

Angiogenesis defines the process in which new vessels grow from existing vessels. Using the mouse retina as a model system, we show that cysteine-rich motor neuron 1 (Crim1), a type I transmembrane protein, is highly expressed in angiogenic endothelial cells. Conditional deletion of the Crim1 gene in vascular endothelial cells (VECs) causes delayed vessel expansion and reduced vessel density. B...

BACKGROUND The pathogenic mechanisms underlying the increased vascular permeability in dengue hemorrhagic fever (DHF) are not well understood. Enhanced cellular immune activation, especially activation of serotype-cross reactive T cells, has been implicated in plasma leakage in DHF. Changes in several biological markers and mediators including cytokines, chemokines, angiogenic factors and their...

Evidence is accumulating that activation of the pancreatic endoplasmic reticulum kinase (PERK) in response to endoplasmic reticulum (ER) stress adapts tumor cells to the tumor microenvironment and enhances tumor angiogenesis by inducing vascular endothelial growth factor A (VEGF-A). Recent studies suggest that VEGF-A can act directly on certain tumor cell types in an autocrine manner, via bindi...