We used a Tet-regulated, oxygen-stable, HIF transgene to create a model of enhanced HIF activity in the adult mammalian heart. Our previous experiments with this inducible model demonstrated progressive cardiac dysfunction as a result of a rapid loss of SERCA2a [
8]. Taken together with our recent findings of rapid, and enhanced neoagnioegensis, it is plausible that stable HIF-1α has an angiogenesis-independent and negative effect on cardiac structure and function. In that study we also showed that although the decrement in contractility was reversible after 3 days of induction, the increase in capillary density persisted at one week after this induction, further supporting an angiogenesis-independent mechanism of cardiac dysfuction. During stable HIF-1α expression in the transgenic mice, the heart dilated and neoangiogenesis was observed. Increased capillary density was detectable after only 3 days of stable HIF-1α expression. This result is consistent with similar results following HIF-1 up-regulation [
16‐
18]. Furthermore, this heightened vascularity persists for at least 7 days after HIF-1α expression had been terminated. This stands in contrast to increased vascularity generated by VEGF over-expression, which rapidly remits following a period of normal VEGF expression [
19]. This persistent enhancement of capillary density by HIF-1 may be a result of more “mature” capillaries generated by the orchestration of several angiogenic molecules and processes. This may also be why we do not see the vascular leakage that occurs with simple VEGF expression. Our casting experiments provide a direct view of HIF-induced angiogenesis, and show that, surprisingly, the initial growth of capillaries can occur directly from relatively large vessels. We also can watch the progression of the nascent capillaries, from a mat of tightly packed small vessels into a more distributed and conventional capillary arrangement. It is encouraging that expression of a stable HIF-1 transgene produces effective angiogenesis in the adult heart, as demonstrated by the perfusion curve analysis. This supports the potential utility of this transcription factor for gene therapy [
20], or other strategies for enhancing HIF activity, such as modulation of prolyl hydroxlases [
21]. Previous studies have demonstrated the angiogenic potential of this molecule, but have modified HIF-1 activity during embryonic development, when vascular structures are growing and remodeling and likely to have greater plasticity. This study establishes the potential for HIF-1 to enhance capillary density after the vasculature has achieved an adult level of stability, and is supported by the temporal expression of pro-angiogenic actors in support of perfuseable neoangiogenesis.