Abstract
Control of microvascular network growth is critical to treatment of ischemic tissue diseases and enhancing regenerative capacity of tissue engineering implants. Conventional therapeutic strategies for inducing angiogenesis aim to deliver one or more pro-angiogenic cytokines or to over-express known pro-angiogenic genes, but seldom address potential compensatory or cooperative effects between signals and the overarching signaling pathways that determine successful outcomes. An emerging grand challenge is harnessing the expanding knowledge base of angiogenic signaling pathways toward development of successful new therapies. We previously performed drug optimization studies by various substitutions of a 2-(2,6-dioxo-3-piperidyl)isoindole-1,3-dione scaffold to discover novel bioactive small molecules capable of inducing growth of microvascular networks, the most potent of which we termed phthalimide neovascularization factor 1 (PNF1, formerly known as SC-3-149). We then showed that PNF-1 regulates the transcription of signaling molecules that are associated with vascular initiation and maturation in a time-dependent manner through a novel pathway compendium analysis in which transcriptional regulatory networks of PNF-1-stimulated microvascular endothelial cells are overlaid with literature-derived angiogenic pathways. In this study, we generated three analogues (SC-3-143, SC-3-263, SC-3-13) through systematic transformations to PNF1 to evaluate the effects of electronic, steric, chiral, and hydrogen bonding changes on angiogenic signaling. We then expanded our compendium analysis toward these new compounds. Variables obtained from the compendium analysis were then used to construct a PLSR model to predict endothelial cell proliferation. Our combined approach suggests mechanisms of action involving suppression of VEGF pathways through TGF-β and NR3C1 network activation.Lay SummaryPreviously, we discovered a novel small molecule (PNF1) that is capable of inducing growth of microvascular networks, a mechanism that is very important in many regenerative applications. In this study, we alter the structure of PNF1 slightly to get three different analogues and focus on gaining insight into how these drugs induce their pro-angiogenic effects. This is done through a few techniques that result in a map of all the transcripts that are up- or downregulated as a result of administering the drug, a knowledge that is necessary for successful therapeutic strategies.Future StudiesAngiogenesis and neovascularization is important in a number of regenerative medicine therapeutics, including soft tissue regeneration. Having a deep understanding of the transcriptional mechanism of small molecules with this angiogenic potential will aid in designing specific immunomodulatory biomaterials. In the future, we will study these drugs and their angiogenic properties in impactful and clinically translatable applications.
Highlights
Despite the recent advancements in drug-induced neovascularization, further development of drug therapies is needed for improvement of functional vessel systems [1]
Lay Summary Previously, we discovered a novel small molecule (PNF1) that is capable of inducing growth of microvascular networks, a mechanism that is very important in many regenerative applications
We discovered a novel small molecule, phthalimide neovascularization factor 1 (PNF-1 or SC-3-149), which is a potent stimulator of microvascular network growth [7]
Summary
Despite the recent advancements in drug-induced neovascularization, further development of drug therapies is needed for improvement of functional vessel systems [1]. Initial efforts for druginduced revascularization have been focused on peptidebased growth factors such as recombinant vascular endothelial growth factor (VEGF) These biological molecules hold significant promise for developing effective therapies for neovascularization; these treatments have many significant drawbacks, including the high cost of protein recovery and purification, as well as susceptibility to aggregation and degradation in the human body [3, 4]. Large doses of these growth factors carry risks of hyperstimulation and angioma formation [5]. For this reason, significant interest is emerging in the use of synthetic small molecules for the induction of angiogenesis [6]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Regenerative Engineering and Translational Medicine
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
