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Background: There is an unmet need for proangiogenic therapeutic molecules for the treatment of tissue ischemia in cardiovascular diseases. However, major inducers of angiogenesis such as vascular endothelial growth factor (VEGF/VEGF-A) have side effects that limit their therapeutic utility in vivo, especially at high concentrations. Angiopoietin-1 has been considered to be a blood vessel stabilization factor that can inhibit the intrinsic property of VEGF to promote vessel leakiness. In this study, we have designed and tested the angiogenic properties of chimeric molecules consisting of receptor-binding parts of VEGF and angiopoietin-1. We aimed at combining the activities of both factors into 1 molecule for easy delivery and expression in target tissues., Methods and Results: The VEGF-angiopoietin-1 (VA1) chimeric protein bound to both VEGF receptor-2 and Tie2 and induced the activation of both receptors. Detailed analysis of VA1 versus VEGF revealed differences in the kinetics of VEGF receptor-2 activation and endocytosis, downstream kinase activation, and VE-cadherin internalization. The delivery of a VA1 transgene into mouse skeletal muscle led to increased blood flow and enhanced angiogenesis. VA1 was also very efficient in rescuing ischemic limb perfusion. However, VA1 induced less plasma protein leakage and myeloid inflammatory cell recruitment than VEGF. Furthermore, angioma-like structures associated with VEGF expression were not observed with VA1., Conclusions: The VEGF-angiopoietin-1 chimera is a potent angiogenic factor that triggers a novel mode of VEGF receptor-2 activation, promoting less vessel leakiness, less tissue inflammation, and better perfusion in ischemic muscle than VEGF. These properties of VA1 make it an attractive therapeutic tool.

Introduction: Ischemic necrosis of the femoral head (INFH) can lead to loss of femoral head architecture and deformity. Moreover, the process of bone healing is intimately associated with angiogenesis. We considered that COMP-Ang1 (an angiogenic factor) might preserve femoral head structure and facilitate bone repair., Methods: INFH was induced in the femoral head of rats by dissecting the cervical periosteum and placing a ligature tightly around the femoral neck. Two weeks later, COMP-Ang1 was injected directly into infarcted areas. Rats were divided into the following groups; 1) the sham-operated group (the sham group), 2) the bovine serum albumin-injected group (the BSA group), and 3) the COMP-Ang1-injected group (the COMP-Ang1 group) (n=20/group). At 8 weeks post-surgery animals were sacrificed and radiologic and histomorphometric assessments were performed., Results: Radiographs obtained at 8 weeks post-surgery showed better preservation of femoral head architecture in the COMP-Ang1 group than in the BSA group. Histological findings and immunostainings of endothelial cells for factor VIII revealed that COMP-Ang1 group animals showed higher levels of vascularity in the secondary ossification center of infarcted femoral heads., Conclusions: When INFH was surgically induced in rats, an intraosseous injection of COMP-Ang1 preserved the trabecular framework of the osseous epiphysis and prevented femoral head deformities by promoting angiogenesis and bone remodeling.

Despite the advent of oral phosphodiesterase-5 inhibitors, curative treatment for erectile dysfunction (ED) remains unavailable. Recently, the link between ED and cardiovascular disease was unveiled and the main etiology of ED was found to be vasculogenic. Therefore, neovascularization is a promising strategy for curing ED. Angiopoietin-1 (Ang1) is an angiogenic growth factor that promotes the generation of stable and functional vasculature. Here, we demonstrate that local delivery of the soluble, stable, and potent Ang1 variant, COMP-Ang1 gene or protein, into the penises of hypercholesterolemic mice increases cavernous angiogenesis, eNOS phosphorylation, and cGMP expression, resulting in full recovery of erectile function and cavernous blood flow up to 8 weeks after treatment. COMP-Ang1-induced promotion of cavernous angiogenesis and erectile function was abolished in Nos3-/- mice and in the presence of the NOS inhibitor, L-NAME. COMP-Ang1 also restored the integrity of endothelial cell-cell junction by down-regulating the expression of histone deacetylase 2 in the penis of hypercholesterolemic mice and in primary cultured mouse cavernous endothelial cells. These findings constitute a new paradigm toward curative treatment of both cavernous angiopathy and ED. [ABSTRACT FROM AUTHOR]