Endothelial progenitor cells (EPCs) are essential in vasculogenesis and wound healing, but their circulating and wound level numbers are decreased in diabetes. This study aimed to determine mechanisms responsible for the diabetic defect in circulating and wound EPCs. Since mobilization of BM EPCs occurs via eNOS activation, we hypothesized that eNOS activation is impaired in diabetes, which results in reduced EPC mobilization. Since hyperoxia activates NOS in other tissues, we investigated whether hyperoxia restores EPC mobilization in diabetic mice through BM NOS activation. Additionally, we studied the hypothesis that impaired EPC homing in diabetes is due to decreased wound level stromal cell-derived factor-1α (SDF-1α), a chemokine that mediates EPC recruitment in ischemia. Diabetic mice showed impaired phosphorylation of BM eNOS, decreased circulating EPCs, and diminished SDF-1α expression in cutaneous wounds. Hyperoxia increased BM NO and circulating EPCs, effects inhibited by the NOS inhibitor N-nitro-l-arginine-methyl ester. Administration of SDF-1α into wounds reversed the EPC homing impairment and, with hyperoxia, synergistically enhanced EPC mobilization, homing, and wound healing. Thus, hyperoxia reversed the diabetic defect in EPC mobilization, and SDF-1α reversed the diabetic defect in EPC homing. The targets identified, which we believe to be novel, can significantly advance the field of diabetic wound healing.

Notch and its ligands play critical roles in cell fate determination. Expression of Notch and ligand in vascular endothelium and defects in vascular phenotypes of targeted mutants in the Notch pathway have suggested a critical role for Notch signaling in vasculogenesis and angiogenesis. However, the angiogenic signaling that controls Notch and ligand gene expression is unknown. We show here that vascular endothelial growth factor (VEGF) but not basic fibroblast growth factor can induce gene expression of Notch1 and its ligand, Delta-like 4 (Dll4), in human arterial endothelial cells. The VEGF-induced specific signaling is mediated through VEGF receptors 1 and 2 and is transmitted via the phosphatidylinositol 3-kinase/Akt pathway but is independent of mitogen-activated protein kinase and Src tyrosine kinase. Constitutive activation of Notch signaling stabilizes network formation of endothelial cells on Matrigel and enhances formation of vessel-like structures in a three-dimensional angiogenesis model, whereas blocking Notch signaling can partially inhibit network formation. This study provides the first evidence for regulation of Notch/Delta gene expression by an angiogenic growth factor and insight into the critical role of Notch signaling in arteriogenesis and angiogenesis

Despite the dramatically increased entry of women into general surgery and surgical subspecialties, traditionally male-dominated fields, there remains a gross under-representation of women in the leadership positions of these departments. Women begin their careers with fewer academic resources and tend to progress through the ranks slower than men. Female surgeons also receive significantly lower salaries than their male counterparts and are more vulnerable to discrimination, both obvious and covert. Although some argue that female surgeons tend to choose their families over careers, studies have actually shown that women are as eager as men to assume leadership positions, are equally qualified for these positions as men, and are as good as men at leadership tasks.Three major constraints contribute to the glass-ceiling phenomenon: traditional gender roles, manifestations of sexism in the medical environment, and lack of effective mentors. Gender roles contribute to unconscious assumptions that have little to do with actual knowledge and abilities of an individuals and they negatively influence decision-making when it comes to promotions. Sexism has many forms, from subtle to explicit forms, and some studies show that far more women report being discriminately against than do men. There is a lack of same-sex mentors and role models for women in academic surgery, thereby isolating female academicians further. This review summarizes the manifestation of the glass-ceiling phenomenon, identifies some causes of these inequalities, and proposes different strategies for continuing the advancement of women in academic surgery and to shatter the glass ceiling.

Most infrarenal AAAs (66%) can be treated with endovascular devices currently available commercially or through US Food and Drug Administration-approved clinical trials. However, patients who are at high risk for surgery and might benefit most from endovascular repair are less likely to qualify for the procedure (49%). Men (70%) are more likely than women (40%) to meet the anatomic criteria for endografting. Difficulties with vascular access and attachment site geometry predominate as reasons for exclusion. Our findings suggest that smaller profile devices, which can negotiate small and tortuous iliac arteries, are needed. Proximal and distal attachment site problems require devices that can accommodate wide and angulated attachment necks and achieve short seal zones.

Mesenchymal stem cells (MSCs) are a heterogeneous population of stem/progenitor cells with pluripotent capacity to differentiate into mesodermal and non-mesodermal cell lineages, including osteocytes, adipocytes, chondrocytes, myocytes, cardiomyocytes, fibroblasts, myofibroblasts, epithelial cells, and neurons. MSCs reside primarily in the bone marrow, but also exist in other sites such as adipose tissue, peripheral blood, cord blood, liver, and fetal tissues. When stimulated by specific signals, these cells can be released from their niche in the bone marrow into circulation and recruited to the target tissues where they undergo in situ differentiation and contribute to tissue regeneration and homeostasis. Several characteristics of MSCs, such as the potential to differentiate into multiple lineages and the ability to be expanded ex vivo while retaining their original lineage differentiation commitment, make these cells very interesting targets for potential therapeutic use in regenerative medicine and tissue engineering. The feasibility for transplantation of primary or engineered MSCs as cellbased therapy has been demonstrated. In this review, we summarize the current knowledge on the signals that control trafficking and differentiation of MSCs.

A key central stage of wound healing requires neovascularization of the wound base granulation tissue. In the adult, neovascularization is now known to occur by both angiogenesis and vasculogenesis. Understanding the biology of these 2 processes offers promising new therapeutic options for patients who suffer from chronic, nonhealing ischemic wounds. The authors review the current literature on the processes of angiogenesis and vasculogenesis and how it relates to wound healing.

We hypothesized that exposure to hyperbaric oxygen (HBO(2)) would mobilize stem/progenitor cells from the bone marrow by a nitric oxide (*NO) -dependent mechanism. The population of CD34(+) cells in the peripheral circulation of humans doubled in response to a single exposure to 2.0 atmospheres absolute (ATA) O(2) for 2 h. Over a course of 20 treatments, circulating CD34(+) cells increased eightfold, although the overall circulating white cell count was not significantly increased. The number of colony-forming cells (CFCs) increased from 16 +/- 2 to 26 +/- 3 CFCs/100,000 monocytes plated. Elevations in CFCs were entirely due to the CD34(+) subpopulation, but increased cell growth only occurred in samples obtained immediately posttreatment. A high proportion of progeny cells express receptors for vascular endothelial growth factor-2 and for stromal-derived growth factor. In mice, HBO(2) increased circulating stem cell factor by 50%, increased the number of circulating cells expressing stem cell antigen-1 and CD34 by 3.4-fold, and doubled the number of CFCs. Bone marrow *NO concentration increased by 1,008 +/- 255 nM in association with HBO(2). Stem cell mobilization did not occur in knockout mice lacking genes for endothelial *NO synthase. Moreover, pretreatment of wild-type mice with a *NO synthase inhibitor prevented the HBO(2)-induced elevation in stem cell factor and circulating stem cells. We conclude that HBO(2) mobilizes stem/progenitor cells by stimulating *NO synthesis.

Diabetic foot disease is a major health problem, which affects 15% of the 200 million patients with diabetes worldwide. Diminished peripheral blood flow and decreased local neovascularization are critical factors that contribute to the delayed or nonhealing wounds in these patients. The correction of impaired local angiogenesis may be a key component in developing therapeutic protocols for treating chronic wounds of the lower extremity and diabetic foot ulcers. Endothelial progenitor cells (EPCs) are the key cellular effectors of postnatal neovascularization and play a central role in wound healing, but their circulating and wound-level numbers are decreased in diabetes, implicating an abnormality in EPC mobilization and homing mechanisms. The deficiency in EPC mobilization is presumably due to impairment of eNOS-NO cascade in bone marrow (BM). Hyperoxia, induced by a clinically relevant hyperbaric oxygen therapy (HBO) protocol, can significantly enhance the mobilization of EPCs from the BM into peripheral blood. However, increased circulating EPCs failed to reach to wound tissues. This is partly a result of downregulated production of SDF-1␣ in local wound lesions with diabetes. Administration of exogenous SDF-1␣ into wounds reversed the EPC homing impairment and, with hyperoxia, synergistically enhanced EPC mobilization, homing, neovascularization, and wound healing.