Arteriogenesis and Therapeutic Angiogenesis

Although advances in therapeutic interventions improved outcomes, vascular occlusive diseases are still challenging not only afflicted but also attending physicians, requiring novel therapeutic strategies. Arteriogenesis, sometimes also called therapeutic angiogenesis, refers to the body’s own capacity to create a natural bypass around a narrowing or occluded arterial vessel. This book gives an insight into current knowledge and advances in vascular sciences and future prospects of therapeutic options. The utility and relevance of circulating biomarkers together with the potential of machine learning methods are discussed as well as the challenges and prospects of novel therapies such as protein- gene-, and stem cell therapy along with multicistronic multigene vectors and the use of microRNAs, exosomes, and secretomes. Vascular smooth muscle phenotype switch as a target to promote arteriogenesis is critically addressed, highlighting the problem of promoting atherosclerosis in parallel. Two articles even deal with cold-inducible RNA-binding protein CIRP/CIRPB presenting it as promising target to promote vascularization concomitant the reduction in ischemic tissue damage. BMPR kinase inhibition is introduced to improve tissue repair in a hereditary form of vascular disorder, and the role of the AP-1 transcription factor JunB in blood vessel formation is described. Some more experimental oriented articles deal with the relevance of choosing the appropriate mouse strain for investigations as well as in vitro Matrigel plug assay as a potent method to investigate angiogenesis. Last but not least, two-photon intravital microscopy is presented as suitable tool to assess plaque angiogenesis in atherosclerotic lesions

Therapeutic angiogenesis for cardiovascular disease

The identification of angiogenic growth factors, such as vascular endothelial growth factor and fibroblast growth factor, has fueled interest in using such factors to induce therapeutic angiogenesis. The results of numerous animal studies and clinical trials have offered promise for new treatment strategies for various ischemic diseases. Increased understanding of the cellular and molecular biology of vessel growth has, however, prompted investigators and clinicians alike to reconsider the complexity of therapeutic angiogenesis. The realization that formation of a stable vessel is a complex, multistep process may provide useful insights into the design of the next generation of angiogenesis therapy

Microporous Biodegradable Films Promote Therapeutic Angiogenesis

Peripheral arterial disease and critical limb ischemia are common symptoms of cardiovascular disease. Vascular surgery is used to create a bypass around occluded blood vessels to improve blood flow to ischemic muscle, thus avoiding the need for amputation. Attempts to vascularize tissues by therapeutic angiogenesis using delivery of exogenous angiogenic agents are underwhelming. A material-based approach that provides an endogenous stimulus capable of promoting angiogenesis and increased tissue perfusion would provide a paradigm shift in treatment options available. It is reported here that microporous biodegradable films produced using thermally induced phase separation provide a localized biophysical stimulus of proangiogenic genes in vivo that is associated with increased blood vessel density and restoration of blood flow to ischemic tissue. These findings show, for the first time, that acellular, nonfunctionalized biodegradable biomaterials can provide an innovative, material-based approach for therapeutic angiogenesis to enhance tissue reperfusion in vivo

Therapeutic Angiogenesis: Foundations and Practical Application

Angiogenesis as therapeutic target has emerged since early works by Judah Folkman, yet his “holy grail” was inhibiting vascular growth to block tumor nutrition. However, in modern biomedicine, “therapeutic angiogenesis” became a large field focusing on stimulation of blood vessel growth for ischemia relief to reduce its detrimental effects in the tissues. In this review, we introduce basic principles of tissue vascularization in response to ischemia exploited in this field. An overview of recent status in therapeutic angiogenesis is given with introduction to emerging technologies, including gene therapy, genetic modification of cells ex vivo and tissue engineering

A biomaterials approach for therapeutic angiogenesis

Peripheral arterial disease (PAD) affects over 200 million people worldwide and can lead to limb ischaemia, amputation and death. Therapeutic angiogenesis aims to promote the formation of new blood vessels in order to treat ischaemia. The programming inherent within cells can be utilised to treat diseases at the cellular level. Adipose derived mesenchymal stem cells (ADMSCs) have been shown to secrete pro-angiogenic proteins, thus could have great potential as a therapy for ischemic disease. In addition, biomaterials can effectively deliver therapeutics to a target site and utilise physical characteristics to influence cell behaviour. Surface topography is known to influence cell alignment, morphology and affect cellular expression of growth factors. This work investigated the effect of surface topography on the secretion of angiogenic growth factors from ADMSCs. Hierarchically structured substrate materials were prepared from poly-DL-lactide-co-glycolide (PLGA) using a thermally induced phase separation (TIPS) process. TIPS materials were characterised using atomic force microscopy to quantify roughness and stiffness, as well as scanning electron microscopy techniques where PLGA processed with TIPS were shown to have higher surface roughness and porosity values. ADMSC proliferation increased on the TIPS-processed substrates compared with the control substrates and the effect of surface topography on the angiogenic secretome of ADMSCs was measured using an in vitro model of angiogenesis, proteomic analysis and measurement of vascular endothelial growth factor (VEGF165). VEGF165 was significantly increased in the supernatants collected from ADMSCs cultured on the TIPS substrate compared with control substrates when normalised for the number of cells. The collected supernatants resulted in increased capillary tubule length, number of capillary junctions and capillary branches in the in vitro angiogenesis assay compared with supernatants collected from control substrates. 5 This work also investigated the effects of TIPS-processed materials implanted in a pre-clinical model of PAD. Laser Doppler imaging revealed an increase in revascularisation in the ischeamic limbs treated TIPS processed materials compared with control materials. Histology and von Willebrand factor staining revealed evidence of blood vessel formation around the implanted TIPS processed materials. This study has shown that ADMSCs seeded onto 2D and 3D TIPS-processed PLGA secreted increased quantities of pro-angiogenic factors in vitro, and when implanted in vivo, TIPS-processed biomaterials improved reperfusion in a pre-clinical model of PAD. These findings open up the opportunity for utilising a unique biomaterial for the treatment of ischemic disease through the promotion of angiogenesis

Spatiotemporal release of VEGF from biodegradable polylactic-co-glycolic acid microspheres induces angiogenesis in chick chorionic allantoic membrane assay

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.While vascular endothelial growth factor (VEGF) is an acknowledged potent pro-angiogenic agent there is a need to deliver it at an appropriate concentration for several days to achieve angiogenesis. The aim of this study was to produce microspheres of biodegradable polylactic-co-glycolic acid (PLGA) tailored to achieve sustained release of VEGF at an appropriate concentration over seven days, avoiding excessive unregulated release of VEGF that has been associated with the formation of leaky blood vessels. Several formulations were examined to produce microspheres loaded with both human serum albumin (HSA) and VEGF to achieve release of VEGF between 3 and 10 ng per ml for seven days to match the therapeutic window desired for angiogenesis. In vitro experiments showed an increase in endothelial cell proliferation in response to microspheres bearing VEGF. Similarly, when microspheres containing VEGF were added to the chorionic membrane of fertilised chicken eggs, there was an increase in the development of blood vessels over seven days in response, which was significant for microspheres bearing VEGF and HSA, but not VEGF alone. There was an increase in both blood vessel density and branching – both signs of proangiogenic activity. Further, there was clearly migration of cells to the VEGF loaded microspheres. In summary, we describe the development of an injectable delivery vehicle to achieve spatiotemporal release of physiologically relevant levels of VEGF for several days and demonstrate the angiogenic response to this. We propose that such a treatment vehicle would be suitable for the treatment of ischemic tissue or wounds

Designing Acellular Injectable Biomaterial Therapeutics for Treating Myocardial Infarction and Peripheral Artery Disease.

As the number of global deaths attributed to cardiovascular disease continues to rise, viable treatments for cardiovascular events such as myocardial infarction (MI) or conditions like peripheral artery disease (PAD) are critical. Recent studies investigating injectable biomaterials have shown promise in promoting tissue regeneration and functional improvement, and in some cases, incorporating other therapeutics further augments the beneficial effects of these biomaterials. In this review, we aim to emphasize the advantages of acellular injectable biomaterial-based therapies, specifically material-alone approaches or delivery of acellular biologics, in regards to manufacturability and the capacity of these biomaterials to regenerate or repair diseased tissue. We will focus on design parameters and mechanisms that maximize therapeutic efficacy, particularly, improved functional perfusion and neovascularization regarding PAD and improved cardiac function and reduced negative left ventricular (LV) remodeling post-MI. We will then discuss the rationale and challenges of designing new injectable biomaterial-based therapies for the clinic

Bone marrow mononuclear cells and acute myocardial infarction

PMCID: PMC3340546This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited