Changing the logic of therapeutic angiogenesis for ischemic disease

Cardiovascular disease (CVD) comprises a range of major clinical cardiac and circulatory diseases, which produce immense health and economic burdens worldwide. Currently, vascular regenerative surgery represents the most employed therapeutic option to treat ischemic disorders, even though not all the patients are amenable to surgical revascularization. Therefore, more efficient therapeutic approaches are urgently required to promote neovascularization. Therapeutic angiogenesis represents an emerging strategy that aims at reconstructing the damaged vascular network by stimulating local angiogenesis and/or promoting de novo blood vessel formation according to a process known as vasculogenesis. In turn, circulating endothelial colony-forming cells (ECFCs) represent truly endothelial precursors, which display high clonogenic potential and have the documented ability to originate de novo blood vessels in vivo. Therefore, ECFCs are regarded as the most promising cellular candidate to promote therapeutic angiogenesis in patients suffering from CVD. The current briefly summarizes the available information about the origin and characterization of ECFCs and then widely illustrates the preclinical studies that assessed their regenerative efficacy in a variety of ischemic disorders, including acute myocardial infarction, peripheral artery disease, ischemic brain disease, and retinopathy. Then, we describe the most common pharmacological, genetic, and epigenetic strategies employed to enhance the vasoreparative potential of autologous ECFCs by manipulating crucial pro-angiogenic signaling pathways, e.g., extracellular-signal regulated kinase/Akt, phosphoinositide 3-kinase, and Ca2+ signaling. We conclude by discussing the possibility of targeting circulating ECFCs to rescue their dysfunctional phenotype and promote neovascularization in the presence of CVD.

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Therapeutic Angiogenesis and Vasculogenesis for Ischemic Disease

Circulation ◽

10.1161/01.cir.0000128596.49339.05 ◽

2004 ◽

Vol 109 (22) ◽

pp. 2692-2697 ◽

Cited By ~ 272

Author(s):

Douglas W. Losordo ◽

Stefanie Dimmeler

Keyword(s):

Therapeutic Angiogenesis ◽

Ischemic Disease

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Therapeutic Angiogenesis of PLGA-Heparin Nanoparticle in Mouse Ischemic Limb

Journal of Nanomaterials ◽

10.1155/2012/193704 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 8

Author(s):

Lishan Lian ◽

Feng Tang ◽

Jing Yang ◽

Changwei Liu ◽

Yongjun Li

Keyword(s):

Surface Morphology ◽

Biological Effects ◽

Average Diameter ◽

Therapeutic Angiogenesis ◽

Release Time ◽

Control Group ◽

Heparin Group ◽

Ischemic Disease ◽

Ischemic Limb ◽

Loading Efficiency

Objective. To evaluate the possibility and efficacy of the nanoparticle encapsulating heparin as a novel delivery system to treat ischemic disease.Methods. Firstly, to synthesize the PLGA heparin and test the surface morphology, the average diameter, the loading efficiency, and the release time in vitro, then inject the PLGA heparin into mouse ischemic limbs to observe the perfusion recovery with LDPI at the time of postischemic 7, 14, 21, and 28 days, and, finally, test the expression of VEGF and HGF, the number of the neovessels and record the necrotic score of ischemic limbs.Results. The surface morphology of the PLGA heparin was smooth, the average diameter was 297 nm, the loading efficiency was 5.35%, and the release period maintained for 14 days. In animal experiment, the perfusion recovery, HGF expression level, and capillary density in PLGA-heparin group were significantly higher than that in control group, and this was consistent with less ischemic limb necrosis.Conclusion. Nanoparticle encapsulating heparin could be successful and efficient in ischemic disease. The therapeutic angiogenesis of PLGA heparin might be due to the prolongation of its biological effects with stimulating growth factor expression.

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Sulfated polysaccharide directs therapeutic angiogenesis via endogenous VEGF secretion of macrophages

Science Advances ◽

10.1126/sciadv.abd8217 ◽

2021 ◽

Vol 7 (7) ◽

pp. eabd8217

Author(s):

Yuanman Yu ◽

Kai Dai ◽

Zehua Gao ◽

Wei Tang ◽

Tong Shen ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Therapeutic Angiogenesis ◽

Sulfated Polysaccharide ◽

Vascular Endothelial ◽

Ischemic Disease ◽

Vegfr2 Signaling ◽

Inflammatory Macrophages ◽

Endothelial Growth Factor ◽

Potential Cancer ◽

Remarkable Progress

Notwithstanding the remarkable progress in the clinical treatment of ischemic disease, proangiogenic drugs mostly suffer from their abnormal angiogenesis and potential cancer risk, and currently, no off-the-shelf biomaterials can efficiently induce angiogenesis. Here, we reported that a semisynthetic sulfated chitosan (SCS) readily engaged anti-inflammatory macrophages and increased its secretion of endogenous vascular endothelial growth factor (VEGF) to induce angiogenesis in ischemia via a VEGF-VEGFR2 signaling pathway. The depletion of host macrophages abrogated VEGF secretion and vascularization in implants, and the inhibition of VEGF or VEGFR2 signaling also disrupted the macrophage-associated angiogenesis. In addition, in a macrophage-inhibited mouse model, SCS efficiently helped to recover the endogenous levels of VEGF and the number of CD31hiEmcnhi vessels in ischemia. Thus, both sulfated group and pentasaccharide sequence in SCS played an important role in directing the therapeutic angiogenesis, indicating that this highly bioactive biomaterial can be harnessed to treat ischemic disease.

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Angiogenesis in Ischemic Disease

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615552 ◽

1999 ◽

Vol 82 (S 01) ◽

pp. 44-52 ◽

Cited By ~ 29

Author(s):

Werner Risau ◽

Hugo H. Marti

Keyword(s):

Growth Factors ◽

Blood Vessel ◽

Vascular Development ◽

Therapeutic Angiogenesis ◽

Angiogenic Factors ◽

Angiogenic Growth Factors ◽

Edema Formation ◽

Ischemic Disease ◽

Naked Dna ◽

Ischemic Diseases

SummaryAngiogenic growth factors and their endothelial receptors function as major regulators of blood vessel formation. The VEGF/VEGFR and the Angiopoietin/Tie2 receptor systems represent key signal transduction pathways involved in the regulation of embryonic vascular development. Inactivation of any of the genes encoding these molecules results in defective vascular development and lethality between embryonic day 8.5 and 12.5. In addition, VEGF and its receptors are also critically involved in the regulation of pathological blood vessel growth in the adult during various angiogenesis-dependent diseases that are associated with tissue hypoxia, such as solid tumor growth and ischemic diseases. It is now well established that therapeutic angiogenesis can be achieved in animal models of hind limb and myocardial ischemia by exogenously adding VEGF and/or other angiogenic growth factors. Available clinical data from human trials also suggests that patients with severe cardiovascular diseases could potentially benefit from such therapies. However, much more work needs to be done to compare the potency of different angiogenic factors or the combination thereof, as well as the best way of delivery, either as recombinant proteins, as naked DNA or via adenoviral vectors. Nevertheless, the therapeutic efficacy of simply injecting naked plasmid DNA or proteins into ischemic tissue to deliver secreted angiogenic factors is an encouraging finding. Time will show whether the adverse side effects of therapeutic angiogenesis, mainly vascular permeability and edema formation, can be minimized and angiogenic factors can be used as an effective therapy in patients for the treatment of ischemic diseases such as arterial occlusive disease, myocardial infarction, and, eventually, also stroke.

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Therapeutic Potential of Endothelial Colony Forming Cells in Ischemic Disease: Strategies to Improve Their Regenerative Efficacy

10.20944/preprints202009.0547.v1 ◽

2020 ◽

Author(s):

Pawan Faris ◽

Sharon Negri ◽

Angelica Perna ◽

Vittorio Rosti ◽

Germano Guerra ◽

...

Keyword(s):

De Novo ◽

Therapeutic Potential ◽

Therapeutic Option ◽

Therapeutic Angiogenesis ◽

Therapeutic Approaches ◽

Ischemic Disease ◽

Endothelial Colony Forming Cells ◽

High Prevalence ◽

Endothelial Precursors

Cardiovascular disease (CVD) comprises a group of heart and circulatory disorders, which are regarded as a global medical issue with high prevalence and mortality rates. Currently, vascular regenerative surgery represents the most employed therapeutic option to treat ischemic disorders, even though not all the patients are amenable to surgical revascularization. Therefore, more efficient therapeutic approaches are urgently required to promote neovascularization. Therapeutic angiogenesis represents an emerging strategy that aims at reconstructing the damaged vascular network by stimulating local angiogenesis and/or promoting de novo blood vessel formation according to a process known as vasculogenesis. Circulating endothelial colony forming cells (ECFCs), in turn, represent truly endothelial precursors able to aggregate into bidimensional tube networks and to originate patent vessels. Accordingly, ECFCs provide the most rationale and promising cellular candidate for therapeutic purposes. The current review provides a brief outline on the origin and characterization of ECFCs and a summary of the progress in preclinical studies aiming at assessing their efficacy in a variety of ischemic disorders, including AMI, PAD, ischemic brain disease and retinopathy. We also describe how to enhance the vasoreparative potential of ECFCs by boosting specific pro-angiogenic signalling pathways either pharmacologically or through gene manipulation. Taken together, these observations suggest that ECFCs represent a useful strategy to treat ischemic diseases.

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The Emerging Role of the Bone Marrow-Derived Stem Cells in (Therapeutic) Angiogenesis

Thrombosis and Haemostasis ◽

10.1055/s-0037-1616226 ◽

2001 ◽

Vol 86 (07) ◽

pp. 289-297 ◽

Cited By ~ 65

Author(s):

Aernout Luttun ◽

Peter Carmeliet

Keyword(s):

Bone Marrow ◽

Smooth Muscle ◽

Smooth Muscle Cells ◽

Muscle Cells ◽

Cell Types ◽

Therapeutic Angiogenesis ◽

Ischemic Disease ◽

Angiogenic Therapy ◽

Bone Marrow Derived Cells

SummaryProper formation of blood vessels (angiogenesis) is essential for development, reproduction and wound healing. When derailed, angiogenesis contributes to numerous lifethreatening disorders. While research has generally been focusing on the two main vascular cell types (endothelial and smooth muscle cells), recent evidence indicates that bone marrow may also contribute to this process, both in the embryo and the adult. Novel vascular progenitors, even one common to both endothelial and smooth muscle cells, have been identified in the embryo. An exciting observation is that endothelial precursors have also been identified in the adult bone marrow. Transplantation studies revealed that these precursors as well as other bone marrow-derived cells contribute to the growth of endothelium-lined vessels (angiogenesis) as well as the expansion of pre-existing collaterals (arteriogenesis) in ischemic disease. These findings have raised hopes that bone marrow-derived cells might one day become useful for cell-based angiogenic therapy.

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Therapeutic Angiogenesis

Vascular and Endovascular Surgery ◽

10.1177/1538574407302849 ◽

2007 ◽

Vol 41 (3) ◽

pp. 173-185 ◽

Cited By ~ 10

Author(s):

Shant M. Vartanian ◽

Rajabrata Sarkar

Keyword(s):

Clinical Trials ◽

Therapeutic Angiogenesis ◽

Peripheral Vascular ◽

Biological Mechanisms ◽

Ischemic Disease ◽

Clinical Applicability ◽

Collateral Artery ◽

Molecular Therapies ◽

Clinical Problems ◽

Proof Of Principle

Myocardial ischemia and peripheral vascular disease persist as significant clinical problems despite improved medical, surgical, and endovascular therapies. Advances in our understanding of the biological mechanisms that govern capillary neovascularization and collateral artery growth have enabled molecular therapies for revascularizing ischemic tissues. Generally known as therapeutic angiogenesis, this review summarizes the essential pre-clinical research and the major clinical trials of molecular therapies for ischemic disease. Early clinical experience has established the proof of principle, however, inconsistent and modest improvements in clinical outcomes have exposed the complexity of neovascularization and problems with transitioning basic science to clinical applicability.

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