title: QHREDGS enhances tube formation, metabolism and survival of endothelial cells in collagen-chitosan hydrogels.
abstract: Cell survival in complex, vascularized tissues, has been implicated as a major bottleneck in advancement of therapies based on cardiac tissue engineering. This limitation motivates the search for small, inexpensive molecules that would simultaneously be cardio-protective and vasculogenic. Here, we present peptide sequence QHREDGS, based upon the fibrinogen-like domain of angiopoietin-1, as a prime candidate molecule. We demonstrated previously that QHREDGS improved cardiomyocyte metabolism and mitigated serum starved apoptosis. In this paper we further demonstrate the potency of QHREDGS in its ability to enhance endothelial cell survival, metabolism and tube formation. When endothelial cells were exposed to the soluble form of QHREDGS, improvements in endothelial cell barrier functionality, nitric oxide production and cell metabolism (ATP levels) in serum starved conditions were found. The functionality of the peptide was then examined when conjugated to collagen-chitosan hydrogel, a potential carrier for in vivo application. The presence of the peptide in the hydrogel mitigated paclitaxel induced apoptosis of endothelial cells in a dose dependent manner. Furthermore, the peptide modified hydrogels stimulated tube-like structure formation of encapsulated endothelial cells. When integrin αvβ3 or α5β1 were antibody blocked during cell encapsulation in peptide modified hydrogels, tube formation was abolished. Therefore, the dual protective nature of the novel peptide QHREDGS may position this peptide as an appealing augmentation for collagen-chitosan hydrogels that could be used for biomaterial delivered cell therapies in the settings of myocardial infarction.
authors.affiliation: The Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Miklas
authors.forename: Susan M
authors.initials: SM
authors.lastname: Dallabrida
authors.forename: Lewis A
authors.initials: LA
authors.lastname: Reis
authors.forename: Nesreen
authors.initials: N
authors.lastname: Ismail
authors.forename: Maria
authors.initials: M
authors.lastname: Rupnick
authors.forename: Milica
authors.initials: M
authors.lastname: Radisic
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D042683:Angiopoietin-1 / Q000737:chemistry*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018914:Cells, Immobilized / Q000166:cytology / Q000378:metabolism; D048271:Chitosan / Q000737:chemistry / Q000494:pharmacology*; D003094:Collagen / Q000737:chemistry / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D020100:Hydrogels / Q000737:chemistry / Q000494:pharmacology*; D039081:Integrin alpha5beta1 / Q000096:biosynthesis; D039302:Integrin alphaVbeta3 / Q000096:biosynthesis; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D020100:Hydrogels; D039081:Integrin alpha5beta1; D039302:Integrin alphaVbeta3; D010455:Peptides; D000255:Adenosine Triphosphate; D003094:Collagen; D048271:Chitosan