Peripheral arterial disease (PAD) represents a spectrum from asymptomatic stenosis to limb-threatening ischemia. The last decade has seen a tremendous increase in the variety of endovascular devices and techniques to treat occlusive disease. Like many evolving technologies, the literature surrounding therapy for endovascular arterial disease consists of mixed-quality manuscripts without clear standardization. Accordingly, critical evaluation of the reported results may be problematic. As such, providers and their patients make treatment decisions without the full benefit of a comparative effectiveness framework. The purpose of this document is to provide a summary for the reporting of endovascular revascularization techniques in the setting of chronic disease. Much of the work in this document is based on prior publications and standards proposed by the Society for Vascular Surgery. We have also made recommendations based on current literature and have attempted to acknowledge shortcomings and areas for future research. The various sections contain summaries of required reporting standards and should serve as a guide for the design of clinical trials and as reference for journal editors and reviewers when considering scientific work pertaining to endovascular therapy for chronic lower extremity arterial disease. An Appendix is provided with commonly used abbreviations in this document.

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Abstract-We show that 1 of the type II bone morphogenetic protein (BMP) receptor ligands, BMP4, is widely expressed in the adult mouse lung and is upregulated in hypoxia-induced pulmonary hypertension (PH). Furthermore, heterozygous null Bmp4 lacZ/ϩ mice are protected from the development of hypoxia-induced PH, vascular smooth muscle cell proliferation, and vascular remodeling. This is associated with a reduction in hypoxia-induced Smad1/5/8 phosphorylation and Id1 expression in the pulmonary vasculature. In addition, pulmonary microvascular endothelial cells secrete BMP4 in response to hypoxia and promote proliferation and migration of vascular smooth muscle cells in a BMP4-dependent fashion. These findings indicate that BMP4 plays a dominant role in regulating BMP signaling in the hypoxic pulmonary vasculature and suggest that endothelium-derived BMP4 plays a direct, paracrine role in promoting smooth muscle proliferation and remodeling in hypoxic PH. Key Words: bone morphogenetic proteins Ⅲ endothelial cells Ⅲ hypoxic pulmonary hypertension Ⅲ signaling pathways Ⅲ Smad Ⅲ vascular remodeling Ⅲ vascular smooth muscle cell proliferation C hronic hypoxia is the most common underlying cause of secondary pulmonary hypertension (PH) in humans. 1 This is associated with the development of fixed defects in the pulmonary vasculature, including medial wall thickening and muscularization of the peripheral vasculature, both mimicked by a rodent model of hypoxic PH in rats and mice. 2,3 Numerous studies using these experimental models provide evidence of an imbalance in the secretion of vasoactive agents and mitogens in the pulmonary vasculature, leading to structural changes in the pulmonary vasculature. 4 -6 Genetic studies in patients with familial primary pulmonary hypertension (FPPH) have identified mutations in 1 of the 3 known type II bone morphogenetic protein receptors (BMP-RII), BMPR2. 7-9 BMP-RII is a member of the transforming growth factor type ␤ family of receptors that acts downstream of the BMP family of ligands. 10,11 BMP ligands interact with 2 classes of transmembrane receptors, termed type I receptors, (ALK2, 3, and 6), and the type II receptors (BMP-RII and Act-RIIA and -IIB). Ligand binding induces type I-receptor phosphorylation by type II receptors, leading to activation of downstream signaling including the classical Smad1/5/8 and the alternative p38 and extracellular signalregulated kinase, mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and protein kinase C pathways. 10,11 Evidence of a role for this signaling pathway in hypoxic PH was shown in 2 recent in vivo studies. By manipulating BMP-RII signaling through 2 different approaches, these studies demonstrated that BMP-RII can promote opposite effects on the pulmonary vasculature under different conditions. 12,13 To explore the mechanisms mediating these effects, we looked at the regulation BMP ligands and downstream signaling in a mouse model of hypoxia-induced PH. One of these ligands, BMP4, is widely expressed in the adult...

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Current strategies for skeletal regeneration often require co-delivery of scaffold technologies, growth factors, and cellular material. However, isolation and expansion of stem cells can be time consuming, costly, and requires an additional procedure for harvest. Further, the introduction of supraphysiologic doses of growth factors may result in untoward clinical side effects, warranting pursuit of alternative methods for stimulating osteogenesis. In this work, we describe a nanoparticulate mineralized collagen glycosaminoglycan scaffold that induces healing of critical-sized rabbit cranial defects without addition of expanded stem cells or exogenous growth factors. We demonstrate that the mechanism of osteogenic induction corresponds to an increase in canonical BMP receptor signalling secondary to autogenous production of BMP-2 and −9 early and BMP-4 later during differentiation. Thus, nanoparticulate mineralized collagen glycosaminoglycan scaffolds may provide a novel growth factor-free and ex vivo progenitor cell culture-free implantable method for bone regeneration.

Skeletal regenerative medicine frequently incorporates deliverable growth factors to stimulate osteogenesis. However, the cost and side effects secondary to supraphysiologic dosages of growth factors warrant investigation of alternative methods of stimulating osteogenesis for clinical utilization. In this work, we describe growth factor independent osteogenic induction of human mesenchymal stem cells (hMSCs) on a novel nanoparticulate mineralized collagen glycosaminoglycan scaffold (MC-GAG). hMSCs demonstrated elevated osteogenic gene expression and mineralization on MC-GAG with minimal to no effect upon addition of BMP-2 when compared to non-mineralized scaffolds (Col-GAG). To investigate the intracellular pathways responsible for the increase in osteogenesis, we examined the canonical and non-canonical pathways downstream from BMP receptor activation. Constitutive Smad1/5 phosphorylation with nuclear translocation occurred on MC-GAG independent of BMP-2, whereas Smad1/5 phosphorylation depended on BMP-2 stimulation on Col-GAG. When non-canonical BMPR signaling molecules were examined, ERK1/2 phosphorylation was found to be decreased in MC-GAG but elevated in Col-GAG. No differences in Smad2/3 or p38 activation were detected. Collectively, these results demonstrated that MC-GAG scaffolds induce osteogenesis without exogenous BMP-2 addition via endogenous activation of the canonical BMP receptor signaling pathway.

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Bone remodeling is a process of continuous resorption and formation/mineralization carried out by osteoclasts and osteoblasts, which, along with osteocytes, comprise the bone multicellular unit (BMU). A key component of the BMU is the bone remodeling compartment (BRC), isolated from the marrow by a canopy of osteoblast-like lining cells. Although much progress has been made regarding the cytokine-dependent and hormonal regulation of bone remodeling, less attention has been placed on the role of extracellular pH (pH(e)). Osteoclastic bone resorption occurs at acidic pH(e). Furthermore, osteoclasts can be regarded as epithelial-like cells, due to their polarized structure and ability to form a seal against bone, isolating the lacunar space. The major ecto-phosphatases of osteoclasts and osteoblasts, acid and alkaline phosphatases, both have ATPase activity with pH optima several units different from neutrality. Furthermore, osteoclasts and osteoblasts express plasma membrane purinergic P2 receptors that, upon activation by ATP, accelerate bone osteoclast resorption and impair osteoblast mineralization. We hypothesize that these ecto-phosphatases help regulate [ATP](e) and localized pH(e) at the sites of bone resorption and mineralization by pH-dependent ATP hydrolysis coupled with P2Y-dependent regulation of osteoclast and osteoblast function. Furthermore, osteoclast cellular HCO3(-), formed as a product of lacunar V-ATPase H(+) secretion, is secreted into the BRC, which could elevate BRC pH(e), in turn affecting osteoblast function. We will review the existing data addressing regulation of BRC pH(e), present a hypothesis regarding its regulation, and discuss the hypothesis in the context of the function of proteins that regulate pH(e).