PR39, a peptide regulator of angiogenesis

Abstract

Although tissue injury and inflammation are considered essential for the induction of angiogenesis, the molecular controls of this cascade are mostly unknown. Here we show that a macrophage-derived peptide, PR39, inhibited the ubiquitin-proteasome-dependent degradation of hypoxia-inducible factor-1alpha protein, resulting in accelerated formation of vascular structures in vitro and increased myocardial vasculature in mice. For the latter, coronary flow studies demonstrated that PR39-induced angiogenesis resulted in the production of functional blood vessels. These findings show that PR39 and related compounds can be used as potent inductors of angiogenesis, and that selective inhibition of hypoxia-inducible factor-1alpha degradation may underlie the mechanism of inflammation-induced angiogenesis.

Myocardial hypertrophy in the absence of external stimuli is induced by angiogenesis in mice

“…To explore the effect of angiogenic stimulation in the adult heart on its vasculature, size, and function, PR39 expression was activated in the hearts of 5-week-old mice. In agreement with previous studies (9), this was associated with an increase in HIF-1α and iNOS expression (Supplemental Figure 1; supplemental material available online with this article; doi:10.1172/JCI32024DS1). Three weeks later, there was a significant increase in the cardiac endothelial cell mass as determined by in vivo perfusion with an I 125 -labeled anti-PECAM antibody ( Figure 1D), with an increase in the capillary count ( Figure 1E) and amount of vasculature per gram of tissue ( Figure 1F).…”

“…PR39 is a secreted peptide that rapidly accumulates in the extracellular matrix and is thought to act via HIF-1α-mediated increase in VEGF and stimulation of fibroblast growth factor signaling (9). The inducible mode of its expression employed in this study allowed us to evaluate a temporal relationship between the onset of angiogenesis and the onset of hypertrophy in the mature heart.…”

“…Previous studies in PR39 transgenic mice demonstrated marked induction of angiogenesis by this growth factor (9). To set up a regulatable myocardial PR39 expression, PR39 gene was placed under control of a tetracycline-responsive element (TRE) promoter sensitive to tetracycline transactivator (tTA) regulated by α-MHC promoter.…”

Gene therapy progress and prospects: therapeutic angiogenesis for limb and myocardial ischemia

“…32 In a study of transgenic mice with porcine PR39 cDNA, angiogenesis was induced in the PR39 mice compared to agematched controls as seen by increased CD-31-stained vascular structures. 22 These results suggest that agents that produce a multifactorial angiogenic response such as HIF-1a and PR39 are effective in neovascularization and may represent a more effective strategy in therapeutic angiogenesis.…”

“…PR39 has been shown to increase the expression of VEGF, the VEGF receptors KDR and FLT-1, and the FGF receptor 1. 22 Concerns over a nonspecific action of PR39 related to charge are being investigated.…”