Evaluación del daño vascular tras el tratamiento con Sunitinib: disfunción endotelial y mecanismos patogénicos implicados
|Author||Reyes Goya, Claudia|
|Director||Vázquez Cueto, Carmen María
Mate Barrero, Alfonso
|Department||Universidad de Sevilla. Departamento de Fisiología|
|Abstract||Sunitinib (Su) is an orally active multitarget tyrosine kin ase inhibitor with
antiangiogenic and antineoplastic effects. Su is the first line choice for metastatic renal
cell carcinoma treatment ( and the second line ...
Sunitinib (Su) is an orally active multitarget tyrosine kin ase inhibitor with antiangiogenic and antineoplastic effects. Su is the first line choice for metastatic renal cell carcinoma treatment ( and the second line one for gastrointestinal stromal tumours (GISTs) and pancreatic neuroendocrine tumour ( pNET). Th e drug binds to several tyrosine kinase receptors including platelet derived growth factor receptor PDGFR α β; colony stimulating factor 1 receptor, CSF 1R; stem cell factor receptor, KIT; Fms like tyrosine kinase 3 receptor, FLT3; vascula r endothelial growth factor receptor, VEGFR 1 2 3; and glial cell line derived neurotrophic factor receptor, RET. A rterial hypertension is a common feature associated to treatment with Su and other VEGFR inhibitors S everal mechanisms have been suggested to explain this side effect , e. reduced nitric oxide generation, endothelial dysfunction, capillary rarefaction or endothelin 1 ove rexpression . However , the precise underlying pathophysiological mechanism s remain unknown. The aim of this doctoral thesis was to deepen our understanding o n those mechanisms involved in the development of Su depen d ent hypertension . To this purpose , our experi m ental approach focused on the stud y o f vascular function, including assays in the presence or absence of circula ting extracellular vesicles. In addition , vascular remodel l ing, fibrosis and inflammation, nicotinamide adenine dinucleoti de phosphate oxidase (NADPH oxidase), oxidative stress and nitric oxide systems were evaluated in thoracic aortas obtained from male Wistar rats treated with Su for 3 weeks. Our results show ed increased blood pressure and reduced endotheliu m dependent vasodilation in animals subjected to Su treatment , the latter being reverted by NADPH ox idase blockade . Interestingly, reduced endothelium dependent vasodilation was also observed in aortic rings of normotensive rats preincubated with circulating extracellular vesicles from Su treated rats, which was reverted by oxidative blockade . Further alterations observed in aortas from Su treated animals included vascular remode l ling and stronge r Masson trichrome staining, together with enhanced immunofluorescence signal for collagen 1 alpha 1 (Col1α1). These results were accompanied by a significant elevation in superoxide anion production and in the activity/protein/gene expression of NADPH oxidase isoforms (NOX1, NOX2 and NOX4), which could be prevented by NOX inhibition. Su treated animals also presented with NOX dependent eNOS inactivation and decrease d aortic NO levels. All these observations indicate that endothelial dysfunction secondary to enhanced oxidative stress and changes in vascular remodel l ing might be responsible for the establishment of arterial hypertension that typically occurs followi n g treatment with Su.
|Citation||Reyes Goya, C. (2021). Evaluación del daño vascular tras el tratamiento con Sunitinib: disfunción endotelial y mecanismos patogénicos implicados. (Tesis Doctoral Inédita). Universidad de Sevilla, Sevilla.|