Browsing by Subject "VEGF"

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  • Licht, Tamar; Kreisel, Tirzah; Biala, Yoav; Mohan, Sandesh; Yaari, Yoel; Anisimov, Andrey; Alitalo, Kari; Keshet, Eli (2020)
    Multiple insults to the brain lead to neuronal cell death, thus raising the question to what extent can lost neurons be replenished by adult neurogenesis. Here we focused on the hippocampus and especially the dentate gyrus (DG), a vulnerable brain region and one of the two sites where adult neuronal stem cells (NSCs) reside. While adult hippocampal neurogenesis was extensively studied with regard to its contribution to cognitive enhancement, we focused on their underestimated capability to repair a massively injured, nonfunctional DG. To address this issue, we inflicted substantial DG-specific damage in mice of either sex either by diphtheria toxin-based ablation of >50% of mature DG granule cells (GCs) or by prolonged brain-specific VEGF overexpression culminating in extensive, highly selective loss of DG GCs (thereby also reinforcing the notion of selective DG vulnerability). The neurogenic system promoted effective regeneration by increasing NSCs proliferation/survival rates, restoring a nearly original DG mass, promoting proper rewiring of regenerated neurons to their afferent and efferent partners, and regaining of lost spatial memory. Notably, concomitantly with the natural age-related decline in the levels of neurogenesis, the regenerative capacity of the hippocampus also subsided with age. The study thus revealed an unappreciated regenerative potential of the young DG and suggests hippocampal NSCs as a critical reservoir enabling recovery from catastrophic DG damage.
  • Osipova, Olga; Sharoyko, Vladimir; Zashikhina, Natalia; Zakharova, Natalya; Tennikova, Tatiana; Urtti, Arto; Korzhikova-Vlakh, Evgenia (2020)
    Polyethyleneimine, poly-L-lysine, chitosan and some others cationic polymers have been thoroughly studied as nucleic acid delivery systems in gene therapy. However, the drug release from these systems proceeds at a very low rate due to extremely high binding between a carrier and gene material. To reduce these interactions and to enhance drug release, we developed a set of amphiphilic polypeptides containing positively and negatively charged amino acids as well as a hydrophobic one. The copolymers obtained were characterized by size-exclusion chromatography, static light scattering, HPLC amino acid analysis and (HNMR)-H-1 spectroscopy. All copolymers formed particles due to a self-assembly in aqueous media. Depending on polypeptide composition, the formation of particles with hydrodynamic diameters from 180 to 900 nm was observed. Stability of polymer particles, loading and release efficiency were carefully studied. Cellular uptake of the particles was efficient and their cytotoxicity was negligible. The application of polymer carriers, containing siRNA, to vascular endothelial growth factor (VEGF-A165) silencing of ARPE-19 cells was successful. The gene silencing was confirmed by suppression of both messenger RNA and protein expression.
  • Theelen, Thomas L.; Lappalainen, Jari P.; Sluimer, Judith C.; Gurzeler, Erika; Cleutjens, Jack P.; Gijbels, Marion J.; Biessen, Erik A. L.; Daemen, Mat J. A. P.; Alitalo, Kari; Yla-Herttuala, Seppo (2015)
    Objective: Angiopoietin-2 (Ang-2) blocking agents are currently undergoing clinical trials for use in cancer treatment. Ang-2 has also been associated with rupture-prone atherosclerotic plaques in humans, suggesting a role for Ang-2 in plaque stability. Despite the availability of Ang-2 blocking agents, their clinical use is still lacking. Our aim was to establish if Ang-2 has a role in atheroma development and in the transition of subclinical to clinically relevant atherosclerosis. We investigated the effect of antibody-mediated Ang-2 blockage on atherogenesis after in a mouse model of atherosclerosis. Methods: Hypercholesterolemic (low-density lipoprotein receptor(-/-) apolipoprotein B-100/100) mice were subjected to high-cholesterol diet for eight weeks, one group with and one group without Ang-2 blocking antibody treatment during weeks 4-8. To enhance plaque development, a peri-adventitial collar was placed around the carotid arteries at the start of antibody treatment. Aortic root, carotid arteries and brachiocephalic arteries were analyzed to evaluate the effect of Ang-2 blockage on atherosclerotic plaque size and stable plaque characteristics. Results: Anti-Ang-2 treatment reduced the size of fatty streaks in the brachiocephalic artery (-72%, p <0.05). In addition, antibody-mediated Ang-2 blockage reduced plasma triglycerides (-27%, p <0.05). In contrast, Ang-2 blockage did not have any effect on the size or composition (collagen content, macrophage percentage, adventitial microvessel density) of pre-existing plaques in the aortic root or collar-induced plaques in the carotid artery. Conclusions: Ang-2 blockage was beneficial as it decreased fatty streak formation and plasma triglyceride levels, but had no adverse effect on pre-existing atherosclerosis in hypercholesterolemic mice. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.
  • Rautiola, Juhana; Lampinen, Anita; Mirtti, Tuomas; Ristimaki, Ari; Joensuu, Heikki; Bono, Petri; Saharinen, Pipsa (2016)
    The Angiopoietin-2 (Ang2, Angpt2) growth factor is a context-dependent antagonist/agonist ligand of the endothelial Tie2 receptor tyrosine kinase and known to promote tumour angiogenesis and metastasis. Angiopoietin antagonists have been tested in clinical cancer trials in combination with VEGF-based anti-angiogenic therapy, including sunitinib, which is widely used as a first-line therapy for metastatic renal cell carcinoma (mRCC). However, little is known about Ang2 protein expression in human tumours and the correlation of tumour Ang2 expression with tumour vascularization, tumour cell proliferation and response to anti-angiogenic therapies. Here, we evaluated, using immunohistochemistry, the expression of Ang2, CD31 and the cell proliferation marker Ki-67 in the primary kidney cancer from 136 mRCC patients, who received first-line sunitinib after nephrectomy. Ang2 protein expression was restrained to RCC tumour vessels, and correlated with tumour vascularization and response to sunitinib. High pre-therapeutic Ang2 expression, and more strongly, combined high expression of both Ang2 and CD31, were associated with a high clinical benefit rate (CBR). Low cancer Ki-67 expression, but not Ang2 or CD31 expression, was associated with favourable progression-free (PFS) and overall survival (OS) as compared to patients with high Ki-67 expression (PFS 6.5 vs. 10.6 months, P = 0.009; OS, 15.7 vs. 28.5 months, P = 0.015). In summary, in this study to investigate endothelial Ang2 in mRCC patients treated with first-line sunitinib, high cancer Ang2 expression was associated with the CBR, but not PFS or OS, whereas low Ki-67 expression was significantly associated with long PFS and OS.
  • Kallio, Pauliina; Jokinen, Elina; Högström, Jenny; Das, Suvendu; Heino, Sarika; Lähde, Marianne; Brodkin, Jefim; Korhonen, Emilia A.; Alitalo, Kari (2020)
    Abnormal vasculature in tumors leads to poor tissue perfusion and cytostatic drug delivery. Although drugs inducing vascular normalization, for example, angiopoietin-2 (Ang2)-blocking antibodies, have shown promising results in preclinical tumor models, clinical studies have so far shown only little efficacy. Because Ang2 is known to play a protective role in stressed endothelial cells, we tested here whether Ang2 blocking could enhance radiation-induced tumor vascular damage. Tumor-bearing mice were treated with anti-Ang2 antibodies every 3 or 4 days starting 3 days before 3 x 2 Gy or 4 x 0.5 Gy whole-body or tumor-focused radiation. Combination treatment with anti-Ang2 and radiation improved tumor growth inhibition and extended the survival of mice with melanoma or colorectal tumors. Single-cell RNA-sequencing revealed that Ang2 blocking rescued radiation-induced decreases inT cells and cells of the monocyte/macrophage lineage. In addition, anti-Ang2 enhanced radiation-induced apoptosis in cultured endothelial cells. In vivo, combination treatment decreased tumor vasculature and increased tumor necrosis in comparison with tumors treated with monotherapies. These results suggest that a combination of Ang2-blocking antibodies with radiation increases tumor growth inhibition and extends the survival of tumor-bearing mice. Significance: These findings offer a preclinical rationale for further testing of the use of radiation in combination with Ang2-blocking antibodies to improve the overall outcome of cancer treatment.
  • Rinne, Sanni J.; Sipilä, Lauri J.; Sulo, Päivi; Jouanguy, Emmanuelle; Beziat, Vivien; Abel, Laurent; Casanova, Jean-Laurent; Parvaneh, Nima; Balighi, Kamran; Guttman-Yassky, Emma; Sarid, Ronit; Aaltonen, Lauri A.; Aavikko, Mervi (2019)
    Familial clustering of classic Kaposi sarcoma (CKS) is rare with, approximately 100 families reported to date. We studied 2 consanguineous families, 1 Iranian and 1 Israeli, with multiple cases of adult CKS and without overt underlying immunodeficiency. We performed genome-wide linkage analysis and whole-genome sequencing to discover the putative genetic cause for predisposition. A 9-kb homozygous intronic deletion in RP11-259O2.1 in the Iranian family and 2 homozygous variants, 1 in SCUBE2 and the other in CDHR5, in the Israeli family were identified as possible candidates. The presented variants provide a robust starting point for validation in independent samples.
  • Erkan, Erdogan Pekcan; Ströbel, Thomas; Dorfer, Christian; Sonntagbauer, Markus; Weinhäusel, Andreas; Saydam, Nurten; Saydam, Okay (2019)
    Meningiomas are primary central nervous system (CNS) tumors that originate from the arachnoid cells of the meninges. Recurrence occurs in higher grade meningiomas and a small subset of Grade I meningiomas with benign histology. Currently, there are no established circulating tumor markers which can be used for diagnostic and prognostic purposes in a non-invasive way for meningiomas. Here, we aimed to identify potential biomarkers of meningioma in patient sera. For this purpose, we collected preoperative (n = 30) serum samples from the meningioma patients classified as Grade I (n = 23), Grade II (n = 4), or Grade III (n = 3). We used a high-throughput, multiplex immunoassay cancer panel comprising of 92 cancer-related protein biomarkers to explore the serum protein profiles of meningioma patients. We detected 14 differentially expressed proteins in the sera of the Grade I meningioma patients in comparison to the age- and gender-matched control subjects (n = 12). Compared to the control group, Grade I meningioma patients showed increased serum levels of amphiregulin (AREG), CCL24, CD69, prolactin, EGF, HB-EGF, caspase-3, and decreased levels of VEGFD, TGF-α, E-Selectin, BAFF, IL-12, CCL9, and GH. For validation studies, we utilized an independent set of meningioma tumor tissue samples (Grade I, n = 20; Grade II, n = 10; Grade III, n = 6), and found that the expressions of amphiregulin and Caspase3 are significantly increased in all grades of meningiomas either at the transcriptional or protein level, respectively. In contrast, the gene expression of VEGF-D was significantly lower in Grade I meningioma tissue samples. Taken together, our study identifies a meningioma-specific protein signature in blood circulation of meningioma patients and highlights the importance of equilibrium between tumor-promoting factors and anti-tumor immunity.
  • Liu, Zehua; Li, Yunzhan; Li, Wei; Lian, Wenhua; Kemell, Marianna; Hietala, Sami; Figueiredo, Patricia; Li, Li; Mäkilä, Ermei; Ma, Ming; Salonen, Jarno; Hirvonen, Jouni T.; Liu, Dongfei; Zhang, Hongbo; Deng, Xianming; Santos, Helder A. (2019)
    Here, an oxidation/acid dual-responsive nanohybrids/ark system was produced. The microfluidics-produced nanohybrids endow the system with an orchestrated cascade from wound detection, reactive oxygen species scavenging, drug release to hydrogel formation. The drug release behavior imitates the dynamic wound healing process, thus rendering an enhanced bio-mimetic regeneration.
  • Sihvo, Hanna-Kaisa (Helsingfors universitet, 2008)
    Equine idiopathic focal eosinophilic enteritis (IFEE) is one form of inflammatory bowel disease. The main clinical signs include colic, weight loss, hypoalbuminemia, acute small intestinal obstruction and pain, occasionally tachycardia and diarrhoea. Macroscopic lesions consist of focal or multifocal erythematous, circumferential bands or circumscribed plaques on the serosal surface of the small intestine. Histological hallmark is a severe focal inflammatory cell infiltration, which is dominated by eosinophils and disrupts the tissue architecture of the small intestine. Neutrophils, haemorrage, necrosis, oedema and activated vascular endothelium represent components of an active inflammatory process, at the same time chronicity is observed as fibroplasia, mononuclear leukocytes and neovascularisation are present in the tissue. Recently it has been suggested that IFEE is a focally exacerbated form of diffuse eosinophilic enteritis (DEE). A wide range of cells in the intestine of horses with IFEE have been shown to express mRNA of eotaxin, which is the major cytokine to recruit eosinophils to the tissue. This study was planned to investigate other significant cytokines in IFEE by examing the expression of interleukin (IL)-4, IL-5, tumor necrosis factor- α (TNF-α), interferon-γ (IFN-γ), transforming growth factor-β (TGF-β) mRNA and vascular endothelial growth factor (VEGF). IL-5 is a major activator of eosinophil differentiation and growth, IL-4 stimulates T cells to differentiate to T helper 2 cells and IFN-γ and TNF-α are known to activate macrophages. TGF-β promotes tissue repair and VEGF induces the proliferation of vascular endothelial cells. IL-5, IFN-γ, TNF-α and TGF-β were successfully amplified by PCR from RNA of a horse with IFEE. IL-4 could not be detected. RNA- in situ hybridisation(ISH) was developed for IFN-γ and TGF-β. 16 IFEE cases, 2 DEE cases and 1 case without any gastrointestinal disorders as a healthy control were included in this study. Mucosal epithelium, lymphocytes, macrophages, fibroblasts, vascular endothelium, eosinophils and neurons of the IFEE cases exhibited positive signals in ISH for IFN-γ and TGF-β mRNA and immunohistochemistry for VEGF. Very similar pattern of positive signals was obtained in ISH of the DEE cases as the IFEE cases. The healthy control case expressed positive signals in epithelium, neurons and vascular endothelium in ISH for IFN-γ mRNA and epithelium and neurons in ISH for TGF-β mRNA.
  • Kivelä, Riikka; Hemanthakumar, Karthik Amudhala; Vaparanta, Katri; Robciuc, Marius; Izumiya, Yasuhiro; Kidoya, Hiroyasu; Takakura, Nobuyuki; Peng, Xuyang; Sawyer, Douglas B.; Elenius, Klaus; Walsh, Kenneth; Alitalo, Kari (2019)
    Background: Heart failure, which is a major global health problem, is often preceded by pathological cardiac hypertrophy. The expansion of the cardiac vasculature, to maintain adequate supply of oxygen and nutrients, is a key determinant of whether the heart grows in a physiological compensated manner or a pathological decompensated manner. Bidirectional endothelial cell (EC)-cardiomyocyte (CMC) cross talk via cardiokine and angiocrine signaling plays an essential role in the regulation of cardiac growth and homeostasis. Currently, the mechanisms involved in the EC-CMC interaction are not fully understood, and very little is known about the EC-derived signals involved. Understanding how an excess of angiogenesis induces cardiac hypertrophy and how ECs regulate CMC homeostasis could provide novel therapeutic targets for heart failure. Methods: Genetic mouse models were used to delete vascular endothelial growth factor (VEGF) receptors, adeno-associated viral vectors to transduce the myocardium, and pharmacological inhibitors to block VEGF and ErbB signaling in vivo. Cell culture experiments were used for mechanistic studies, and quantitative polymerase chain reaction, microarrays, ELISA, and immunohistochemistry were used to analyze the cardiac phenotypes. Results: Both EC deletion of VEGF receptor (VEGFR)-1 and adeno-associated viral vector-mediated delivery of the VEGFR1-specific ligands VEGF-B or placental growth factor into the myocardium increased the coronary vasculature and induced CMC hypertrophy in adult mice. The resulting cardiac hypertrophy was physiological, as indicated by preserved cardiac function and exercise capacity and lack of pathological gene activation. These changes were mediated by increased VEGF signaling via endothelial VEGFR2, because the effects of VEGF-B and placental growth factor on both angiogenesis and CMC growth were fully inhibited by treatment with antibodies blocking VEGFR2 or by endothelial deletion of VEGFR2. To identify activated pathways downstream of VEGFR2, whole-genome transcriptomics and secretome analyses were performed, and the Notch and ErbB pathways were shown to be involved in transducing signals for EC-CMC cross talk in response to angiogenesis. Pharmacological or genetic blocking of ErbB signaling also inhibited part of the VEGF-B-induced effects in the heart. Conclusions: This study reveals that cross talk between the EC VEGFR2 and CMC ErbB signaling pathways coordinates CMC hypertrophy with angiogenesis, contributing to physiological cardiac growth.
  • Björkstén, Sofie (Helsingfors universitet, 2011)
    Angiogenesis, the formation of new blood vessels from preexisting vascular network, is an essential process during tumor development. Growing tumors secrete different growth factors that induce angiogenesis, of which vascular endothelial growth factor (VEGF) is predominant. Angiogenesis inhibitors act either by blocking the extracellular bindning of growth factor to its receptor by monoclonal antibodies or by blocking the intracellular signalling pathway by small-molecule agents. The small-molecule agent sunitinib is a multitargeted tyrosine kinase inhibitor that has antiangiogenic and antitumor activities due to the selective inhibition of several tyrosine kinase receptors. Sunitinib is approved for treatment of gastrointestinal stromal tumors, renal cell carcinoma and pancreatic neuroendocrine tumors. Known side effects are hypertension, cardiotoxicity and renal damage. These toxic effects are due to sunitinibs "off-target" toxicity, which occurs when a tyrosine kinase inhibitor causes adverse effects via inhibiton of a kinase not intended to be a target of the drug. For example inhibition by sunitinib of AMPK, a kinase that plays key roles in maintaining metabolic homeostasis in the heart, accounts in part for the toxicity seen in cardiomyocytes exposed to sunitinib. By achieving a better understandning of what causes the side effects it could be possible to develop treatments that reduce off-target effects. Caloric restriction is one nonpharmacological approach that has been shown to have beneficial effects on the heart partly by activating sirtuins. Sirtuins regulate a diverse array of cellular functions, including metabolism, gene transcription, cell division and cellular stress response. The aim for this study was to investigate whether caloric restriction improves sunitinib-induced cardiovascular toxicity and renal damage in rats, and to study activated cellular pathways. In this study 40 spontaneously hypertensive rats (SHR) and 10 normotensive Wistar-Kyoto (WKY) rats were used. They were divided into groups depending on treatment; I WKY control, II SHR control, III SHR + caloric restriction 70 %, IV SHR + sunitinib 3 mg/kg and V SHR sunitinib 3 mg/kg + caloric restriction 70 %. The follow-up period was eigth weeks. Blood pressure was messured weekly, metabolic cages were used week 4 and week 8 for urine samples, echocardiography was performed the last week and vascular response was studied at the end. The proteins Sirt1 and AMPK in heart were investigated by Western blot and the amount of the marker of macrofage ED1 in kidney by immunohistochemistry. Based on this study it was observed that the dose 3 mg/kg sunitinib was well tolerated in rats because it did not cause more extensive hypertension, worse hypertrophy or renal damage compared to untreated SHR groups. This study also showed that short-term caloric restriction has beneficial cardiovascular effects.
  • Kähkönen, Mikael; Tuuminen, Raimo; Aaltonen, Vesa (2021)
    Background To evaluate the incidence of sustained elevation of intraocular pressure (SE-IOP) associated with intravitreal injections of anti-vascular endothelial growth factors (anti-VEGF) bevacizumab and aflibercept in patients with wet age-related macular degeneration (wAMD). Methods A retrospective cohort study consisting of 120 eyes from 120 patients with anti-VEGF treatment for wAMD. Three different anti-VEGF groups were considered: i) 71 cases receiving bevacizumab only, ii) 49 cases receiving bevacizumab before switch to aflibercept, iii) 49 cases after switch to aflibercept. 120 uninjected fellow eyes served as controls. SE-IOP was defined as an increase from baseline >= 5 mmHg on 2 consecutive follow-up visits. The incidence of SE-IOP was analysed using exact Poisson tests and survival analysis. The time course of IOP was evaluated with linear mixed effect modelling. Results In total, 6 treated eyes (2.38% incidence per eye-year) and 9 fellow eyes (3.58% incidence per eye-year) developed SE-IOP, and survival analysis showed no statistically significant difference (p = 0.43). Furthermore, the incidence of SE-IOP did not differ between the three anti-VEGF groups. Comparing the injected eyes of patients under 70 years to those of patients over 70 years, there was a statistically significant difference in survival without SE-IOP (incidence of 16.7% vs 0.7%, respectively, p < 0.0001). Conclusion Intravitreal anti-VEGF injections were not associated with sustained elevation of IOP. These results do not support the claim that repeated anti-VEGF injections could elevate IOP.
  • Suominen, Janne S.; Lampela, Hanna; Heikkila, Paivi; Lohi, Jouko; Jalanko, Hannu; Pakarinen, Mikko P. (2014)
  • Guryanov, Ivan; Tennikova, Tatiana; Urtti, Arto (2021)
    Vascular endothelial growth factors (VEGFs) are the family of extracellular signaling proteins involved in the processes of angiogenesis. VEGFA overexpression and altered regulation of VEGFA signaling pathways lead to pathological angiogenesis, which contributes to the progression of various diseases, such as age-related macular degeneration and cancer. Monoclonal antibodies and decoy receptors have been extensively used in the anti-angiogenic therapies for the neutralization of VEGFA. However, multiple side effects, solubility and aggregation issues, and the involvement of compensatory VEGFA-independent pro-angiogenic mechanisms limit the use of the existing VEGFA inhibitors. Short chemically synthesized VEGFA binding peptides are a promising alternative to these full-length proteins. In this review, we summarize anti-VEGFA peptides identified so far and discuss the molecular basis of their inhibitory activity to highlight their pharmacological potential as anti-angiogenic drugs.
  • Bono, Petri; Massard, Christophe; Peltola, Katriina J.; Azaro, Analia; Italiano, Antoine; Kristeleit, Rebecca S.; Curigliano, Giuseppe; Lassen, Ulrik; Arkenau, Hendrik-Tobias; Hakulinen, Pasi; Garratt, Chris; Ikonen, Tarja; Mustonen, Mika V. J.; Rodon, Jordi A. (2020)
    Background Genetic alterations in fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR) signalling are observed in various tumours. We report a first-in-human phase I/IIa trial evaluating tolerability, pharmacokinetics and preliminary antitumour activity of ODM-203, a novel FGFR and VEGFR inhibitor. Methods Open-label, non-randomised, multicentre, phase I/IIa dose escalation and expansion study in patients with advanced or metastatic solid tumours. Results Overall, 84 patients received treatment; optimal tablet dose was found to be 400 mg/day with food. All patients experienced at least one adverse event; the majority (89.2%) were grade 1 or 2% and 70.4% were considered treatment related. The most commonly reported events were bilirubin increase-related events (75%) and diarrhoea (50%). Overall response rate was 9.2% and median progression-free survival was 16.1 and 12.4 weeks for patients with aberrant or non-aberrant FGFR tumours. Median time on treatment was 10.1 weeks for all patients and 14.5 weeks for patients who received 400 mg tablets. Conclusion This study suggests ODM-203 400 mg/day results in sufficient plasma concentrations and acceptable tolerability in most patients. Preliminary signs of therapeutic activity of ODM-203 in patients with solid tumours was observed.
  • Bellou, Sofia; Karali, Evdoxia; Bagli, Eleni; Al-Maharik, Nawaf; Morbidelli, Lucia; Ziche, Marina; Adlercreutz, Herman; Murphy, Carol; Fotsis, Theodore (2012)
  • Karaman, Sinem; Leppänen, Veli-Matti; Alitalo, Kari (2018)
    Vascular endothelial growth factors (VEGFs) are best known for their involvement in orchestrating the development and maintenance of the blood and lymphatic vascular systems. VEGFs are secreted by a variety of cells and they bind to their cognate tyrosine kinase VEGF receptors (VEGFRs) in endothelial cells to elicit various downstream effects. In recent years, there has been tremendous progress in elucidating different VEGF/VEGFR signaling functions in both the blood and lymphatic vascular systems. Here, and in the accompanying poster, we present key elements of the VEGF/VEGFR pathway and highlight the classical and newly discovered functions of VEGF signaling in blood and lymphatic vessel development and pathology.