Highly-efficient morphogens for guided angiogenesis

• Main Author: Verdenelli, Maria
• Published: University of Brighton 2018
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.754057

Coronary artery disease and stroke are leading causes of mortality in Europe, resulting in a loss of function of the affected tissue. One of the challenges is to restore the myocardium tissue functionality using growth-factors mimicking peptides to stimulate the development of pre-existing blood vessels to enhance tissue regeneration and ensure tissue viability. In this research, hyperbranched peptides based on poly (ɛ-lysine) (i.e. dendrons) of different branching generations (Gx) were used as protein scaffolds to present, at their uppermost branching generation, peptide analogues for key growth factors such as the Angiopoietin-1 (Ang-1), the Vascular Endothelial growth factor (VEGF) or the Platelet Derived growth factor (PDGF-BB). The resulting dendritic angiogenic peptides have been designed specifically to target myocardial ischemic tissue starting from a molecular root [diphenilalanine (FF)] capable of being retained for longer times within the target tissue by interacting with the extracellular matrix (ECM) through hydrophobic interactions and being decorated with the specific angiogenic bioactive peptide analogues capable of inducing a precise biological response in targeting cells. Synthesis of the dendritic angiogenic peptides was performed using an established solid phase method by a manual method and characterised by analytical HPLC, Mass Spectrometry and FT-IR. The angiogenic potential of dendritic angiogenic peptides has been evaluated by a 2D in vitro model where the human umbilical vein endothelial cells (HUVECs) were spiked with the soluble linear and dendritic analogues resulting in an endothelial sprouting. Successively, dendritic angiogenic peptides have been used as functionalisation molecules for collagen type I engineered as either injectable biomaterials (beads) or cardiac patches (scaffolds). The potential of these novel synthesised molecules in inducing angiogenesis in vitro when covalently grafted to the biomaterial surfaces also showed an angiogenic potential demonstrating that the bioactivity is not confined to their soluble form. However, their bioactivity in both soluble and grafted form was shown to depend on the molecular branching of the dendron and relative availability of the bioactive sequences. Indeed, the present study for the first time unveils a novel biomaterial approach to stimulate angiogenesis through nano-structured biomaterials and emphasise the need for a finely spaced presentation of the relevant peptide sequence to obtain established endothelial sprouting.