Angiogenesis and vasculogenesis: Inducing the growth of new blood vessels and wound healing by stimulation of bone marrow–derived progenitor cell mobilization and homing

During embryonic development, the vasculature is among the first organs to form and is in charge of maintaining metabolic homeostasis by supplying oxygen and nutrients and removing waste products. As one would expect, blood vessels are critical not only for organ growth in the embryo but also for repair of wounded tissue in the adult. An imbalance in angiogenesis (a time-honored term that globally refers to the growth of new blood vessels) contributes to the pathogenesis of numerous malignant, inflammatory, ischemic, infectious, immune, and wound-healing disorders. This review focuses on the central role of the growth of new blood vessels in ischemic and diabetic wound healing and defines the most current nomenclature that describes the neovascularization process in wounds. There are now two well-defined, distinct, yet interrelated processes for the formation of postnatal new blood vessels, angiogenesis, and vasculogenesis. Reviewed are recent new data on vasculogenesis that promise to advance the field of wound healing

Targeted cell delivery of mesenchymal stem cell therapy for cardiovascular disease applications: a review of preclinical advancements

Cardiovascular diseases (CVD) continue to be the leading cause of morbidity and mortality globally and claim the lives of over 17 million people annually. Current management of CVD includes risk factor modification and preventative strategies including dietary and lifestyle changes, smoking cessation, medical management of hypertension and cholesterol lipid levels, and even surgical revascularization procedures if needed. Although these strategies have shown therapeutic efficacy in reducing major adverse cardiovascular events such as heart attack, stroke, symptoms of chronic limb-threatening ischemia (CLTI), and major limb amputation significant compliance by patients and caregivers is required and off-target effects from systemic medications can still result in organ dysfunction. Stem cell therapy holds major potential for CVD applications but is limited by the low quantities of cells that are able to traffic to and engraft at diseased tissue sites. New preclinical investigations have been undertaken to modify mesenchymal stem cells (MSCs) to achieve targeted cell delivery after systemic administration. Although previous reviews have focused broadly on the modification of MSCs for numerous local or intracoronary administration strategies, here we review recent preclinical advances related to overcoming challenges imposed by the high velocity and dynamic flow of the circulatory system to specifically deliver MSCs to ischemic cardiac and peripheral tissue sites. Many of these technologies can also be applied for the targeted delivery of other types of therapeutic cells for treating various diseases

A Molecular and Clinical Review of Stem Cell Therapy in Critical Limb Ischemia

Peripheral artery disease (PAD) is one of the major vascular complications in individuals suffering from diabetes and in the elderly that can progress to critical limb ischemia (CLI), portending significant burden in terms of patient morbidity and mortality. Over the last two decades, stem cell therapy (SCT) has risen as an attractive alternative to traditional surgical and/or endovascular revascularization to treat this disorder. The primary benefit of SCT is to induce therapeutic neovascularization and promote collateral vessel formation to increase blood flow in the ischemic limb and soft tissue. Existing evidence provides a solid rationale for ongoing in-depth studies aimed at advancing current SCT that may change the way PAD/CLI patients are treated

Limb interventions in patients undergoing treatment with an unsupported bifurcated aortic endograft system: A review of the Phase II EVT Trial

AbstractIntroduction: Both supported and unsupported bifurcated endograft limbs develop flow-restricting lesions, including kinks, stenoses, and occlusions, which can be identified during or after surgery. Recognition and intervention are essential to achieve long-term graft patency and a satisfactory functional result. This report represents a comprehensive retrospective review of graft limb interventions from the Phase II EVT Trial with the Endovascular Grafting System unsupported bifurcated endograft (Guidant/EVT, Menlo Park, Calif). Methods: The study population consists of 242 patients who underwent treatment with bifurcated endografts implanted during the EVT Phase II Trial. Graft limb interventions have been divided into two groups: those in whom the intervention occurred during surgery versus those in whom the intervention occurred after surgery. Parameters studied included type, incidence, and timing of graft limb intervention, indications for intervention, procedures performed, and overall patient outcome. Results: The mean follow-up period was 31 months. Primary, primary assisted, and secondary limb patency rates were 61.6%, 93.7%, and 97.1%, respectively. Technical success rate at case completion was 97.5%. In 68 of the 242 cases, limb interventions were performed during surgery to assure patency (28.1%). In 28 cases, interventions were performed after surgery (11.6%). Of these postoperative limb problems, 82% occurred during the first 6 months. Repeat limb interventions were necessitated in three patients (1.2%). Within the intraoperative intervention group, perceived indications included kinks (15%), stenosis (57%), dissection (6%), graft redundancy (12%), and instances of twists, thrombosis, and pressure gradients (10%). These findings were successfully managed with percutaneous transluminal angioplasty only (41%), percutaneous transluminal angioplasty and stent (50%), and various combined interventions. Within the postoperative intervention group, symptomatic indications included stenosis (46%) and thrombosis/occlusion (54%). These postoperative limb events were successfully managed with stent (64%), thrombolysis (32%), and femoral-femoral bypass (21%). When limb dysfunction developed in the postoperative setting, it most often occurred within the first 6 months of implantation. Only one patient in this Phase II cohort had a lower extremity amputation unrelated to a graft limb abnormality. Conclusion: The unsupported bifurcated limbs of this endograft necessitated primary adjunctive intervention in 40% of cases. Primary intervention was two times more likely to be performed at the time of the implant rather than after surgery. Repeat limb interventions were not common. Endograft limb flow problems were successfully treated with standard endovascular or surgical interventions or both. These data may support prophylactic stenting of unsupported Ancure graft limbs. A strategy that includes both intraoperative and early postoperative graft limb surveillance is essential to detect reduced limb flow. (J Vasc Surg 2002;36:118-26.

Gender-related differences in infrarenal aortic aneurysm morphologic features: Issues relevant to Ancure and Talent endografts

AbstractPurpose: The purpose of this study was to determine whether gender-related anatomic variables may reduce applicability of aortic endografting in women. Methods: Data on all patients evaluated at our institution for endovascular repair of their abdominal aortic aneurysm were collected prospectively. Ancure (Endovascular Technologies (EVT)/Guidant Corporation, Menlo Park, Calif) and Talent (World Medical/Medtronic Corporation, Sunrise, Fla) endografts were used. Preoperative imaging included contrast-enhanced computed tomography and arteriography or magnetic resonance angiography. Results: One hundred forty-one patients were evaluated (April 1998–December 1999), 19 women (13.5%) and 122 men (86.5%). Unsuitable anatomy resulted in rejection of 63.2% of the women versus only 33.6% of the men (P = .026). Maximum aneurysm diameter in women and men were similar (women, 56.94 ± 8.23 mm; men, 59.29 ± 13.22 mm; P = .5). The incidence of iliac artery tortuosity was similar across gender (women, 36.8%; men, 54.9%; P = .2). The narrowest diameter of the larger external iliac artery in women was significantly smaller (7.29 ± 2.37 mm) than in men (8.62 ± 2.07 mm; P = .02). The proximal neck length was significantly shorter in women (10.79 ± 12.5 mm) than in men (20.47 ± 19.5 mm; P = .02). The proximal neck width was significantly wider in women (30.5 ± 2.4 mm) than in men (27.5 ± 2.5 mm; P = .013). Proximal neck angulation (>60 degrees) was seen in a significantly higher proportion of women (21%) than men (3.3%; P = .012). Of the patients accepted for endografting, a significantly higher proportion of women required an iliofemoral conduit for access (women, 28.6%; men, 1.2%; P = .016). Conclusion: Gender-related differences in infrarenal aortic aneurysm morphologic features may preclude widespread applicability of aortic endografting in women, as seen by our experience with the Ancure and Talent devices. In addition to a significantly reduced iliac artery size, women are more likely to have a shorter, more dilated, more angulated proximal aortic neck. (J Vasc Surg 2001;33:S77-84.

Inhibition of Fibroblast Growth by Notch1 Signaling Is Mediated by Induction of Wnt11-Dependent WISP-1

Fibroblasts are an integral component of stroma and important source of growth factors and extracellular matrix (ECM). They play a prominent role in maintaining tissue homeostasis and in wound healing and tumor growth. Notch signaling regulates biological function in a variety of cells. To elucidate the physiological function of Notch signaling in fibroblasts, we ablated Notch1 in mouse (Notch1Flox/Flox) embryonic fibroblasts (MEFs). Notch1-deficient (Notch1−/−) MEFs displayed faster growth and motility rate compared to Notch1Flox/Flox MEFs. Such phenotypic changes, however, were reversible by reconstitution of Notch1 activation via overexpression of the intracellular domain of Notch1 (NICD1) in Notch1-deficient MEFs. In contrast, constitutive activation of Notch1 signaling by introducing NICD1 into primary human dermal fibroblasts (FF2441), which caused pan-Notch activation, inhibited cell growth and motility, whereas cellular inhibition was relievable when the Notch activation was countered with dominant-negative mutant of Master-mind like 1 (DN-MAML-1). Functionally, “Notch-activated” stromal fibroblasts could inhibit tumor cell growth/invasion. Moreover, Notch activation induced expression of Wnt-induced secreted proteins-1 (WISP-1/CCN4) in FF2441 cells while deletion of Notch1 in MEFs resulted in an opposite effect. Notably, WISP-1 suppressed fibroblast proliferation, and was responsible for mediating Notch1's inhibitory effect since siRNA-mediated blockade of WISP-1 expression could relieve cell growth inhibition. Notch1-induced WISP-1 expression appeared to be Wnt11-dependent, but Wnt1-independent. Blockade of Wnt11 expression resulted in decreased WISP-1 expression and liberated Notch-induced cell growth inhibition. These findings indicated that inhibition of fibroblast proliferation by Notch pathway activation is mediated, at least in part, through regulating Wnt1-independent, but Wnt11-dependent WISP-1 expression

Disorders of the Abdominal Aorta and Major Branches

Diseases of the subdiaphragmatic aorta in the pediatric ­population constitute a rare and highly heterogeneous group of disorders that present a tremendous challenge and require a multidisciplinary treatment approach. When viewed from the broad perspective of vascular surgical diagnosis and treatments, these conditions can be separated into two distinct entities: aneurysmal disease and stenotic/occlusive disease. Effective vascular reconstruction in these patients must take into account highly specialized issues related to the small size of the vessels being reconstructed, the limited availability of effective conduit for reconstruction, the optimal timing for operative repair, the anticipated life-long length of follow-up, and the principles of surgical technique that need to be incorporated to accommodate for anticipated growth. Equally important, the biology of the underlying specific diagnosis and the need for optimal medical therapy, family counseling, and social services must be understood, instituted, and carefully monitored by a team that, in our experience, has required the expertise of not only the pediatric and vascular surgeons, but also geneticists, nephrologists, rheumatologists, cardiologists, pediatric intensive care specialists, interventional radiologists, neurologists, gastroenterologists, neurosurgeons, plastics/microvascular surgeons, and transplantation surgeons