Critical role of microenvironmental factors in angiogenesis

Department of Research, Basel University Hospital, Hebelstrasse 20, 4031 Basel, Switzerland.
Current Atherosclerosis Reports (Impact Factor: 3.42). 06/2005; 7(3):227-34. DOI: 10.1007/s11883-005-0011-7
Source: PubMed


Therapeutic angiogenesis, which entails the induction of new blood vessels by the delivery of angiogenic growth factors, is a highly attractive approach to the treatment of ischemic diseases. However, it is becoming increasingly clear that this is not easily achieved, as the effects of angiogenic growth factors can differ markedly depending on the timing of their expression, on the shape of the concentration gradients they form in vivo, and the inter-actions between endothelial cells and pericytes they induce. In fact, the same dose of vascular endothelial growth factor can induce stable, nonleaky, pericyte-covered normal capillaries or aberrant vascular structures that develop into hemangiomas. This difference in outcome can be due solely to the spatial characteristics of the delivery method. If delivery allows a homogeneous spatial distribution of VEGF in the microenvironment around each producing cell, angiogenesis can be therapeutic, whereas if the total dose is the average of diverse spatial levels, aberrant angiogenesis cannot be avoided. To achieve therapeutic angiogenesis, a means of regulating the microenvironmental levels of angiogenic factors will be critical to the generation of effective new treatment strategies.

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    • "In fact, due to the ECM-binding of VEGF, different GF concentrations remain tightly localized after secretion and a few " hotspots " of high expression can cause angioma growth even if the total dose is rather low. Therefore, the same total dose of VEGF can have disparate effects, therapeutic or toxic, depending on whether it is distributed homogeneously in the tissue or not (Banfi et al., 2005). On the other hand, sufficient duration of VEGF expression for at least about 4 weeks is also critical for newly induced vessels to stabilize and persist (Dor et al., 2002; Ozawa et al., 2004; Tafuro et al., 2009). "
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    ABSTRACT: Blood vessel growth plays a key role in regenerative medicine, both to restore blood supply to ischemic tissues and to ensure rapid vascularization of clinical-size tissue-engineered grafts. For example, vascular endothelial growth factor (VEGF) is the master regulator of physiological blood vessel growth and is one of the main molecular targets of therapeutic angiogenesis approaches. However, angiogenesis is a complex process and there is a need to develop rational therapeutic strategies based on a firm understanding of basic vascular biology principles, as evidenced by the disappointing results of initial clinical trials of angiogenic factor delivery. In particular, the spatial localization of angiogenic signals in the extracellular matrix (ECM) is crucial to ensure the proper assembly and maturation of new vascular structures. Here, we discuss the therapeutic implications of matrix interactions of angiogenic factors, with a special emphasis onVEGF, as well as provide an overview of current approaches, based on protein and biomaterial engineering that mimic the regulatory functions of ECM to optimize the signaling microenvironment of vascular growth factors.
    Full-text · Article · Apr 2015 · Frontiers in Bioengineering and Biotechnology
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    • "Increasing evidence suggests that the apparent paradox between the crucial biological function of VEGF and its lack of a therapeutic window may be due to the difficulty of appropriately controlling its dosage distribution in vivo (Banfi et al., 2005; Ozawa et al., 2004). In fact, VEGF has the potential to induce significant adverse effects, such as increased blood vessel permeability with edema (Thurston et al., 2000) and aberrant vascular proliferation (Schwarz et al., 2000; Springer et al., 1998) if even rare ''hotspots'' of excessive expression are not avoided (Ozawa et al., 2004). "
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    ABSTRACT: Vascular Endothelial Growth Factor (VEGF) can induce normal angiogenesis or the growth of angioma-like vascular tumors depending on the amount secreted by each producing cell, as it remains localized in the microenvironment. In order to control the distribution of VEGF expression levels in vivo, we recently developed a high-throughput FACS-based technique to rapidly purify transduced progenitors that homogeneously express a specific VEGF dose from a heterogeneous primary population. Here we tested the hypothesis that cell-based delivery of a controlled VEGF level could induce normal angiogenesis in the heart, while preventing the development of angiomas. Freshly isolated human adipose-tissue stem cells (ASC) were transduced with retroviral vectors expressing either rat VEGF linked to a FACS-quantifiable cell-surface marker (a truncated form of CD8), or CD8 alone as control (CTR). VEGF-expressing cells were FACS-purified to generate populations producing either a specific VEGF level (SPEC) or uncontrolled heterogeneous levels (ALL). Fifteen nude rats underwent intra-myocardial injection of 107 cells. Histology was performed after 4 weeks. Both the SPEC and ALL cells produced a similar total amount of VEGF and both cell types induced a 50%-60% increase in both total and perfused vessel density compared to CTR cells, despite very limited stable engraftment. However, homogeneous VEGF expression by SPEC cells induced only normal and stable angiogenesis. Conversely, heterogeneous expression of a similar total amount by the ALL cells caused the growth of numerous angioma-like structures. These results suggest that controlled VEGF delivery by FACS-purified ASC may be a promising strategy to achieve safe therapeutic angiogenesis in the heart.
    Full-text · Article · Oct 2012 · Human Gene Therapy

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