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. 2013 Oct 1;9(4):261-72.
doi: 10.4161/org.25970. Epub 2013 Aug 8.

Hypoxia-based Strategies for Angiogenic Induction: The Dawn of a New Era for Ischemia Therapy and Tissue Regeneration

Free PMC article

Hypoxia-based Strategies for Angiogenic Induction: The Dawn of a New Era for Ischemia Therapy and Tissue Regeneration

Ektoras Hadjipanayi et al. Organogenesis. .
Free PMC article


Therapeutic angiogenesis promises to aid the healing and regeneration of tissues suffering from a compromised vascular supply. Ischaemia therapy has so far primarily focused on delivering isolated angiogenic growth factors. The limited success of these strategies in clinical trials, however, is increasingly forcing researchers to recognize the difficulties associated with trying to mimic the angiogenic process, due to its natural complexity. Instead, a new school of thought is gradually emerging, focusing on how to induce angiogenesis at its onset, by utilizing hypoxia, the primary angiogenic stimulus in physiological, as well pathological states. This shift in therapeutic approach is underlined by the realization of the importance of depressed HIF-1 α-mediated gene programming in non-healing ischemic tissues, which could explain their apparent habituation to chronic hypoxic stress and the limited capacity to generate adaptive angiogenesis. Hypoxia-based strategies, then effectively aim to override the habituated angiogenic cellular response, re-start the regenerative process and drive it to completion. Here we make a distinction between those strategies that utilize hypoxia in vitro as a preconditioning tool to optimize the angiogenic potential of tissue/cells before transplantation, vs. strategies that aim to induce hypoxia-induced signaling in vivo, directly, through pharmacological means or gene transfer. We then discuss possible future directions for the field, as it moves into the phase of clinical trials.

Keywords: HIF1 stabilization; Ischaemia; angiogenesis; gene transfer; hypoxia; pre-conditioning; therapy.


Figure 1. Flow diagram showing the chronological development of strategies targeting therapeutic angiogenesis for tissue ischemia. Following the limited success of single factor (primarily VEGF) administration in clinical trials, hypoxia-based strategies have emerged (dotted line) as a new approach that promises to provide a solution to inducing a robust, yet physiological angiogenic response, while avoiding the common side effects associated with mono-therapy. Strategies shown above the time axis represent those therapies that focus on directly inducing hypoxia-mediated angiogenic signaling in vivo, while strategies shown below the axis are those based on in vitro hypoxic pre-conditioning before in vivo cell/tissue transplantation. On the right end of the axis, a range of newer strategies are presented, which are likely to play a key role as the field moves into the phase of clinical trials.
Figure 2. Schematic showing the chronological progression of the physiological, and then pathological processes, that set in following an ischemic event. A multi-modal therapeutic strategy (shown in italics) should focus at first providing immediate angiogenic support by delivering of on-demand available factor protein mixtures, obtained from in vitro pre-conditioned hypoxic cell cultures, in order to prevent the regression of newly-formed vessels and permanent tissue damage, resulting from a gradual reduction in cellular response to chronic hypoxic stress (dashed line). At the same time, chemical HIF stabilization and/or induction of HIF-mediated signaling through gene transfer will ensure a continuous supply of angiogenic factors, to sustain tissue repair/regeneration. At a later stage, transplantation of hypoxia pre-conditioned cells can aid in re-establishing a healthy, angiogenic cell population at the target site, so that similar future episodes can be prevented. The therapeutic timeline of this approach (t2), therefore follows in ‘reverse’ order the timeline of the physiological tissue response to hypoxia (t1), thus stimulating/supporting angiogenesis, and driving it to completion.

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