Abstract
Angiogenesis is an important physiological process playing a crucial role in wound healing and cancer progression. Vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) are key players in angiogenesis. Based on previous findings regarding the modulation of VEGF activity by glycosaminoglycans (GAG), here we explore the interaction of hyaluronan (HA)-based GAG with PDGF and its receptor PDGFR-β by applying molecular modeling and dynamics simulations in combination with surface plasmon resonance (SPR). Computational analysis on the interaction of oligo-hyaluronan derivatives with different sulfation pattern and functionalization shows that these GAG interact with PDGF in relevant regions for receptor recognition, and that high sulfation as well as modification with the TAMRA group convey stronger binding. On the other hand, the studied oligo-hyaluronan derivatives are predicted to scarcely recognize PDGFR-β. SPR results are in line with the computational predictions regarding the binding pattern of HA tetrasaccharide (HA4) derivatives to PDGF and PDGFR-β. Furthermore, our experimental results also show that the complexation of PDGF to PDGFR-β can be modulated by HA4 derivatives. The results found open the path for considering HA4 derivatives as potential candidates to be exploited for modulation of the PDGF/PDGFR-β signaling system in angiogenesis and related disease conditions.
Highlights
Platelet-derived growth factors (PDGF) are important proteins acting as potent mitogens for connective tissue cells such as fibroblasts and smooth muscle cells and, in turn, regulating processes such as embryonic development and tissue regeneration (Kohler and Lipton 1974; Ross et al 1974)
Based on previous findings regarding the modulation of Vascular endothelial growth factor (VEGF) activity by glycosaminoglycans (GAG), here we explore the interaction of hyaluronan (HA)-based GAG with platelet derived growth factor (PDGF) and its receptor PDGFR-β by applying molecular modeling and dynamics simulations in combination with surface plasmon resonance (SPR)
Considering the dual axis control of angiogenesis by the interplay of the VEGF and PDGF systems (Bai et al 2018; Mamer et al 2017), and based on our previous studies on the modulation of VEGF-mediated angiogenic processes by GAG (Koehler et al 2019), here we investigate the molecular recognition of several oligo-hyaluronan derivatives by PDGF-BB and PDGFR-β in atomic detail taking into account the structural and functional similarity between PDGF and VEGF
Summary
Platelet-derived growth factors (PDGF) are important proteins acting as potent mitogens for connective tissue cells such as fibroblasts and smooth muscle cells and, in turn, regulating processes such as embryonic development and tissue regeneration (Kohler and Lipton 1974; Ross et al 1974). PDGF interacts with its corresponding receptors PDGFR-α and PDGFR-β to carry out distinct functions. PDGFR-α is involved in the signaling controlling gastrulation and in the development of various organs including intestine, lung, skin, kidney and testis; whereas PDGFR-β signaling is well established in the process of early hematopoiesis and blood vessel formation (Andrae et al 2008). PDGF-BB is a ligand for PDGFR-β, which is relevant in angiogenesis. Enhanced PDGF/PDGFR signaling is observed in a variety of disease conditions such as cancer, pulmonary fibrosis and atherosclerosis (Ostman 2004). Due to the significance of the signaling of the PDGF/PDGFR system, its inhibition has become an attractive strategy, for instance, in anti-cancer therapy (Gialeli et al 2014)
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