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Hereditary angioedema (HAE) is an autosomal dominant disease characterized by deficiency of C1 inhibitor (C1-INH) that commonly presents with recurrent swelling affecting different parts of the body. Supplementation with C1-INH is successfully used to treat HAE in selected countries, mostly in Europe. Berinert P (CSL Behring, Marburg, Germany), a human plasma-derived C1-INH, was studied in the International Multicenter Prospective Angioedema C1-inhibitor Trial 1 (IMPACT1) that was completed in 2007. It was the first safety and dose-finding study of C1-INH in patients with acute abdominal and facial angioedema. IMPACT2 was the extension of the first trial to study C1-INH efficacy and safety in multiple treatments of acute HAE attacks in various areas of the body. Berinert P has excellent potential to become a first-line therapy for treating patients with acute HAE attacks in the USA and other countries involved in the IMPACT trials. While final data from the IMPACT2 trial are not yet released, this article reviews currently available data from previous reports and abstract presentations.

Vascular remodeling is a common feature of many vasculopathies, including graft arteriosclerosis (GA). We investigated whether endothelial and smooth muscle cell-derived neuropilin-like protein (ESDN) is a marker of vascular remodeling in GA. Immunostaining of human coronary arteries demonstrated high levels of ESDN in GA, but not in normal arteries. In a model of GA, where a segment of human coronary is transplanted into a severe combined immunodeficient mouse, followed by allogeneic human peripheral blood mononuclear cell (PBMC) reconstitution, ESDN was minimally expressed in transplanted human arteries in the absence of reconstitution. By 2 weeks following PBMC reconstitution, at a time corresponding to maximal vascular cell proliferation, high levels of ESDN were detected in the transplanted arteries. Similarly, injury-induced vascular remodeling in apoE(-/-) mice was associated with early and transient ESDN upregulation, in parallel with cell proliferation. In vascular smooth muscle cell (VSMC) cultures, ESDN expression was significantly higher in proliferating, as compared to growth-arrested cells. ESDN overexpression in VSMC led to a decline in growth curves, while ESDN knock down had the opposite effect. We conclude that ESDN is a marker of vascular remodeling and regulator of VSMC proliferation. ESDN may serve as a therapeutic or diagnostic target for GA.

Graft arteriopathy (GA), characterized by diffuse concentric narrowing of coronary arteries, is the major cause of late graft failure in cardiac transplantation. alphavbeta3 Integrin is up-regulated in proliferating vascular cells and may constitute an appropriate target for imaging GA. We used a human/mouse chimeric model of GA, in which segments of human coronary artery were transplanted to severe combined immunodeficiency mice, followed by reconstitution with allogeneic human peripheral blood mononuclear cells (PBMC). This led to vascular remodeling characterized by neointima formation over a period of 4 wk. alphavbeta3 expression in the graft was minimal in animals without PBMC, considerably increased by 2 wk, and decreased toward baseline by 4 wk after PBMC reconstitution. Cell proliferation was maximal at 2 wk, correlating with peak alphavbeta3 expression. RP748, an 111In-labeled alphavbeta3 (active conformation)-targeted radiotracer was injected into groups of 5 recipients at 0, 2, and 4 wk after PBMC reconstitution. Relative uptakes, defined as autoradiographic intensity in the graft/native aortas closely tracked the proliferative process. Specificity of uptake was demonstrated using excess nonlabeled tracer. In conclusion, alphavbeta3 integrin is transiently up-regulated (and activated) in GA and may be targeted by RP748 for detection of the proliferative process in early GA.

Background: The alpha(v)beta3 integrin plays a critical role in cell proliferation and migration. We hypothesized that vascular cell proliferation, a hallmark of injury-induced remodeling, can be tracked by targeting alpha(v)beta3 integrin expression in vivo., Methods and Results: RP748, a novel 111In-labeled alpha(v)beta3-specific radiotracer, was evaluated for its cell-binding characteristics and ability to track injury-induced vascular proliferation in vivo. Three groups of experiments were performed. In cultured endothelial cells (ECs), TA145, a cy3-labeled homologue of RP748, localized to alpha(v)beta3 at focal contacts. Activation of alpha(v)beta3 by Mn2+ led to increased EC binding of TA145. Left common carotid artery wire injury in apolipoprotein E-/- mice led to vascular wall expansion over a period of 4 weeks. RP748 (7.4 MBq) was injected into groups of 9 mice at 1, 3, or 4 weeks after left carotid injury, and carotids were harvested for autoradiography. Relative autographic intensity, defined as counts/pixel of the injured left carotid area divided by counts/pixel of the uninjured right carotid area, was higher at 1 and 3 weeks (1.8+/-0.1 and 1.9+/-0.2, respectively) and decreased significantly by 4 weeks after injury (1.4+/-0.1, P<0.05). Carotid alpha(v) and beta3 integrin expression was maximal at 1 week and decreased by 4 weeks after injury. The proliferation index, as determined by Ki67 staining, followed a temporal pattern similar to that of RP748 uptake. Dynamic gamma imaging demonstrated rapid renal clearance of RP748., Conclusions: RP748 has preferential binding to activated alpha(v)beta3 integrin and can track the injury-induced vascular proliferative process in vivo.

The hallmark of endothelial activation, an early and critical step in many alloimmune and inflammatory responses, is the transcriptional induction and expression of endothelial adhesion molecules (eg, vascular cell adhesion molecule-1 [VCAM-1]). We assessed the feasibility of VCAM-1-targeted in vivo detection of endothelial activation using I-125-labeled-F(ab')2 fragments of E1/6, a monoclonal antibody against human but not murine VCAM-1. The Kd and Bmax, determined by saturation binding in tumor necrosis factor (TNF)-activated human endothelial cells (ECs), were 3.2 +/- 0.6 nmol/L and 5600 +/- 300 binding sites per EC, respectively. Biodistribution and in vivo binding characteristics of I-125-E1/6 F(ab')2 were assessed in a novel chimeric human/mouse model, in which human skin (as a source of human microvasculature) is grafted onto SCID/beige mice. I-125-E1/6 F(ab')2 localized to TNF-activated human skin grafts as detected by autoradiography and gamma well-counting. Relative uptakes (uptake in human skin graft/uptake in the surrounding mouse skin) were, respectively, 2.6 +/- 0.8 (n = 14) and 1.6 +/- 0.3 (n = 12) for E1/6 and MOPC-21, an isotype-matched control antibody (P < .01). The preferential uptake in human skin graft was not due to differences in tissue vascularity assessed by Tc-99m-labeled murine red blood cells. In conclusion, the chimeric human/mouse model is a novel experimental tool for in vivo evaluation of human endothelial cell-specific radiopharmaceuticals. Although I-125-E1/6 F(ab')2 localized to human skin grafts, the limited number of VCAM-1 molecules/endothelial cell adversely affects its suitability as a target for in vivo imaging of endothelial activation., (Copyright 2004 Elsevier Inc.)

Noninvasive imaging strategies will be critical for defining the temporal characteristics of angiogenesis and assessing efficacy of angiogenic therapies. The alphavbeta3 integrin is expressed in angiogenic vessels and represents a potential novel target for imaging myocardial angiogenesis. We demonstrated the localization of an indium-111-labeled ((111)In-labeled) alphavbeta3-targeted agent in the region of injury-induced angiogenesis in a chronic rat model of infarction. The specificity of the targeted alphavbeta3-imaging agent for angiogenesis was established using a nonspecific control agent. The potential of this radiolabeled alphavbeta3-targeted agent for in vivo imaging was then confirmed in a canine model of postinfarction angiogenesis. Serial in vivo dual-isotope single-photon emission-computed tomographic (SPECT) imaging with the (111)In-labeled alphavbeta3-targeted agent demonstrated focal radiotracer uptake in hypoperfused regions where angiogenesis was stimulated. There was a fourfold increase in myocardial radiotracer uptake in the infarct region associated with histological evidence of angiogenesis and increased expression of the alphavbeta3 integrin. Thus, angiogenesis in the heart can be imaged noninvasively with an (111)In-labeled alphavbeta3-targeted agent. The noninvasive evaluation of angiogenesis may have important implications for risk stratification of patients following myocardial infarction. This approach may also have significant clinical utility for noninvasively tracking therapeutic myocardial angiogenesis.