Stanley G. Rockson

Endothelial cell diversity revealed by global expression profiling.

The vascular system is locally specialized to accommodate widely varying blood flow and pressure and the distinct needs of individual tissues. The endothelial cells (ECs) that line the lumens of blood and lymphatic vessels play an integral role in the regional specialization of vascular structure and physiology. However, our understanding of EC diversity is limited. To explore EC specialization on a global scale, we used DNA microarrays to determine the expression profile of 53 cultured ECs. We found that ECs from different blood vessels and microvascular ECs from different tissues have distinct and characteristic gene expression profiles. Pervasive differences in gene expression patterns distinguish the ECs of large vessels from microvascular ECs. We identified groups of genes characteristic of arterial and venous endothelium. Hey2, the human homologue of the zebrafish gene gridlock, was selectively expressed in arterial ECs and induced the expression of several arterial-specific genes. Several genes critical in the establishment of left/right asymmetry were expressed preferentially in venous ECs, suggesting coordination between vascular differentiation and body plan development. Tissue-specific expression patterns in different tissue microvascular ECs suggest they are distinct differentiated cell types that play roles in the local physiology of their respective organs and tissues.

Lymphedema: classification, diagnosis and therapy

This review presents the diagnostic features, the pathophysiology and the available therapies for lymphedema. This disease is often able to be diagnosed by its characteristic cliniccal presentation, yet, in some cases, ancillary tests might be necessary to establish the diagnosis, particularly in the early stages of the disease and in edemas of mixed etiology. These diagnostic modalities are also useful in clinical studies. Available modalities include isotopic lymphoscintigraphy, indirect and direct lymphography, magnetic resonance imaging, computed tomography and ultrasonography. Lymphedema may be primary or secondary to the presence of other diseases and/or to the consequences of surgery. Primary lymphedema may occur at any phase of life but it most commonly appears at puberty. Secondary lymphedema is encountered more often. The most prevalent worldwide cause of lymphedema is filariasis, which is particularly common in south-east Asia. In the USA, postsurgical lymphedema of the extremity prevails. Complications of chronic limb lymphedema include recurrent cellulitis and lymphangiosarcoma. Most patients are treated conservatively, by means of various forms of compression therapy, including complex physical therapy, pneumatic pumps and compressive garments. Volume reducing surgery is performed rarely. Lymphatic microsurgery is still in an experimental stage, although a few centers consistently report favorable outcomes.

Therapeutic lymphangiogenesis with human recombinant VEGF-C

Chronic regional impairments of the lymphatic circulation often lead to striking architectural abnormalities in the lymphedematous tissues. Lymphedema is a common, disabling disease that currently lacks a cure. Vascular endothelial growth factors C and D mediate lymphangiogenesis through the VEGFR‐3 receptor on lymphatic endothelia. The purpose of this study was to investigate the therapeutic potential for lymphangiogenesis with VEGF‐C. We developed a rabbit ear model to simulate human chronic postsurgical lymphatic insufficiency. Successful, sustained surgical ablation of the ear lymphatics was confirmed by water displacement volumetry. After complete healing, the experimental animals (n=8) received a single, s.c. 100 μg dose of VEGF‐C in the operated ear; controls (n=8) received normal saline. Radionuclide lymphoscintigraphy was performed to quantitate lymphatic function. Immunohistochemistry (IHC) was performed 7–8 days following treatment. After VEGF‐C, there was a quantifiable amelioration of lymphatic function. IHC confirmed a significant increase in lymphatic vascularity, along with reversal of the intense tissue hypercellularity of untreated lymphedema. This study confirms the capacity of a single dose of VEGF‐C to induce therapeutic lymphangiogenesis in acquired lymphedema. In addition to improving lymphatic function and vascularity, VEGF‐C can apparently reverse the abnormalities in tissue architecture that accompany chronic lymphatic insufficiency.

The role of chemokines in human cardiovascular pathology: enhanced biological insights

A growing body of experimental evidence supports the pivotal role of chemokines in the pathogenesis of vascular disease. The endothelial expression of monocyte chemoattractant protein-1 (MCP-1) is apparently essential for the earliest cellular responses of atherogenesis. Many atherogenic and anti-atherogenic stimuli can be construed to exert their effects predominantly upon MCP-1 expression within the vascular wall. The atherogenic effects of interleukin-8 (IL-8) seem to be mediated through the down-regulation of the tissue inhibitor of metalloproteinase-1 (TIMP-1). Biological expression of these two important vascular chemokines is further modulated by NF-kappaB. The delineation of these molecular forces that drive atherogenesis increasingly underscores the pivotal role of various chemokines. It is anticipated that more precise delineation of these patterns of gene expression will help to identify molecular targets for the prevention and treatment of atherosclerosis.

Estimating the Population Burden of Lymphedema

Lymphedema is a complex, regional edematous state that ensues when lymph transport is insufficient to maintain tissue homeostasis. The disorder is remarkably prevalent, but the population implications of lymphatic dysfunction are not well‐studied. Prevalence estimates for lymphedema are relatively high, yet its prevalence is likely underestimated. The ability to estimate the burden of disease poses profound implications for current and future lymphedema patients, but the challenge to correctly surmise the incidence and prevalence of lymphedema is complex and the relevant medical literature is scanty. In the absence of the highly desired, prospectively designed and rigorously performed relevant epidemiologic studies, it is instructive to look at the existing studies of lymphedema disease burden. In the current review, the extant literature is examined in the context of the disease setting in which tissue edema is encountered. Incidence or prevalence estimates are provided or inferred, and, where feasible, the size of the subject population is also identified. It is extremely attractive to contemplate that future approaches will entail formal, prospectively designed studies to objectively quantitate incidence and prevalence statistics for individual categories, as well as for the global lymphedema population.

Coronary restenosis: a review of mechanisms and management

Percutaneous coronary interventions represent an attractive alternative to surgical revascularization; nevertheless, these techniques continue to be characterized by their propensity to elicit restenosis. Despite an exhaustive search for an effective pharmacotherapy to treat or prevent restenosis, hundreds of clinical trials have failed to identify an agent with proven therapeutic benefit. Recently, however, the Food and Drug Administration approved intracoronary radiation (brachytherapy) as a viable therapeutic option for in-stent stenosis. In addition, recent randomized trials have shown encouraging results for drug-eluting stents. This article reviews the pathophysiology of restenosis, along with current and future treatment options.

Inflammatory manifestations of experimental lymphatic insufficiency.

Background Sustained lymph stagnation engenders a pathological response that is complex and not well characterized. Tissue inflammation in lymphedema may reflect either an active or passive consequence of impaired immune traffic. Methods and Findings We studied an experimental model of acute post-surgical lymphedema in the tails of female hairless, immunocompetent SKH-1 mice. We performed in vivo imaging of impaired immune traffic in experimental, murine acquired lymphatic insufficiency. We demonstrated impaired mobilization of immunocompetent cells from the lymphedematous region. These findings correlated with histopathological alterations and large-scale transcriptional profiling results. We found intense inflammatory changes in the dermis and the subdermis. The molecular pattern in the RNA extracted from the whole tissue was dominated by the upregulation of genes related to acute inflammation, immune response, complement activation, wound healing, fibrosis, and oxidative stress response. Conclusions We have characterized a mouse model of acute, acquired lymphedema using in vivo functional imaging and histopathological correlation. The model closely simulates the volume response, histopathology, and lymphoscintigraphic characteristics of human acquired lymphedema, and the response is accompanied by an increase in the number and size of microlymphatic structures in the lymphedematous cutaneous tissues. Molecular characterization through clustering of genes with known functions provides insights into processes and signaling pathways that compose the acute tissue response to lymph stagnation. Further study of genes identified through this effort will continue to elucidate the molecular mechanisms and lead to potential therapeutic strategies for lymphatic vascular insufficiency.

Decongestive lymphatic therapy for patients with cancer-related or primary lymphedema

PURPOSE A prospective evaluation was undertaken to assess the efficacy of intensive, short-term decongestive lymphatic therapy coupled with focused patient instruction in long-term self-care for the management of lymphedema. METHODS The therapeutic responses of 79 patients with lymphedema were analyzed prospectively. Each patient received intensive, short-term decongestive lymphatic therapy, with quantification of the extent and durability of the clinical response. Decongestive lymphatic therapy was performed by therapists trained in these techniques. The mean (+/-SD) duration of therapy was 8+/-3 days. Instruction in self-management techniques was incorporated into the therapeutic regimen by day 3 of the patients treatment. The mean period of follow-up was 38+/-52 days. Changes in the volume of the affected limb were assessed with a geometric approximation derived from serial measurements of circumference along the axis of the limb. RESULTS The mean short-term reduction in limb volume was 44%+/-62% of the excess volume in the upper extremities and 42%+/-40% in the lower extremities. At follow-up, these results were adequately sustained: mean long-term excess volume reductions of 38%+/-56% (upper extremities) and 41%+/-27% (lower extremities) were observed. CONCLUSION Decongestive lymphatic therapy, combined with long-term self-management, is efficacious in treating patients with lymphedema of the extremity.

Lymphedema: anatomy, physiology and pathogenesis

The authors review the current understanding of lymphatic anatomy and physiology, and the pathophysiology of lymphedema. The skin lymphatic system consists of the initial lymphatics, which converge into lymphatic precollectors, collectors and lymphatic ducts; these in turn convey the lymph to the regional lymph nodes. Interstitial fluid and particles enter the initial lymphatics through interendothelial openings and by vesicular transport. Lymphatic uptake is enhanced by external compression. Lymphatic transport depends greatly on contraction of lymphangions, which generate the suction force that promotes absorption of interstitial fluid and expels lymph to collecting ducts. In lymphedema, various types of congenital and acquired abnormalities of lymphatic vessels and lymph nodes have been observed. These often lead to lymphatic hypertension, valvular insufficiency and lymphostasis. Accumulation of interstitial and lymphatic fluid within the skin and subcutaneous tissue stimulates fibroblasts, keratinocytes and adipocytes eventuating in the deposition of collagen and glycosaminoglycans within the skin and subcutaneous tissue together with skin hypertrophy and destruction of elastic fibers.

Myocarditis in systemic lupus erythematosus

Although clinical manifestations of myocarditis in systemic lupus erythematosus are uncommon, noninvasive cardiac testing may detect subclinical cases. The pathogenesis of myocarditis in systemic lupus erythematosus has been ascribed to many factors, including autoimmunity, medications, and coexisting diseases. Lupus myocarditis merits urgent clinical attention because of the likely progression to arrhythmias, conduction disturbances and heart block, dilated cardiomyopathy, and heart failure. Endomyocardial biopsy can be used to identify the underlying inflammatory histopathology. Usual therapy includes high-dose corticosteroids, in addition to standard cardiac medications.