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 left͞right 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 is a dreaded complication of cancer treatment. However, despite the fact that >5 million Americans are affected by this disorder, the development of effective treatments is limited by the fact that the pathology of lymphedema remains unknown. The purpose of these studies was to determine the role of inflammatory responses in lymphedema pathology. Using mouse models of lymphedema, as well as clinical lymphedema specimens, we show that lymphatic stasis results in a CD4 T-cell inflammation and T-helper 2 (Th2) differentiation. Using mice deficient in T cells or CD4 cells, we show that this inflammatory response is necessary for the pathological changes of lymphedema, including fibrosis, adipose deposition, and lymphatic dysfunction. Further, we show that inhibition of Th2 differentiation using interleukin-4 (IL-4) or IL-13 blockade prevents initiation and progression of lymphedema by decreasing tissue fibrosis and significantly improving lymphatic function, independent of lymphangiogenic growth factors. We show that CD4 inflammation is a critical regulator of tissue fibrosis and lymphatic dysfunction in lymphedema and that inhibition of Th2 differentiation markedly improves lymphatic function independent of lymphangiogenic cytokine expression. Notably, preventing and/or reversing the development of pathological tissue changes that occur in lymphedema may be a viable treatment strategy for this disorder.
Generalized Lymphatic Dysplasia (GLD) is a rare form of primary lymphedema characterized by a uniform, widespread lymphedema affecting all segments of the body, with systemic involvement such as intestinal and/or pulmonary lymphangiectasia, pleural effusions, chylothoraces and/or pericardial effusions. This may present prenatally as non-immune hydrops. Here we report homozygous and compound heterozygous mutations in PIEZO1 resulting in an autosomal recessive form of GLD with a high incidence of non-immune hydrops fetalis (NIHF) and childhood onset of facial and four limb lymphedema. Mutations in PIEZO1, which encodes a mechanically activated ion channel, have been reported with autosomal dominant Dehydrated Hereditary Stomatocytosis (DHS) and non-immune hydrops of unknown etiology. Besides its role in red blood cells, our findings indicate that PIEZO1 is also involved in the development of lymphatic structures.
Lymphedema is a complication of cancer treatment occurring in approximately 50% of patients who undergo lymph node resection. Despite its prevalence, the etiology of this disorder remains unknown. In this study, we determined the effect of soft tissue fibrosis on lymphatic function and the role of transforming growth factor (TGF)-1 in the regulation of this response. We determined TGF- expression patterns in matched biopsy specimens collected from lymphedematous and normal limbs of patients with secondary lymphedema. To determine the role of TGF- in regulating tissue fibrosis, we used a mouse model of lymphedema and inhibited TGF- function either systemically with a monoclonal antibody or locally by using a Lymphedema is a dreaded complication of cancer management that results from the disruption of lymphatic channels. It is estimated that 3 to 5 million Americans have chronic lymphedema and suffer from chronic swelling, recurrent infections, pain, impaired function, and decreased quality of life.1-4 Remarkably, despite the prevalence and morbidity of lymphedema, there is currently no known cure and treatment remains primarily symptomatic in nature with the goal of preventing disease progression. Patients are required to wear tight, uncomfortable garments for the rest of their lives and risk worsening of the condition with repeated infections. 5The development of effective treatment options for lymphedema has been hampered by the fact that the etiology of this disorder remains poorly understood. Thus, although it is clear that the initiating event in postsurgical lymphedema is injury to the lymphatic channels, it is unknown why some patients develop this complication while others who are identically treated do not. In addition, it remains unknown why lymphedema develops in some patients after seemingly trivial lymphatic injury. None of the authors have any commercial associations or financial relationships that would create a conflict of interest with the work presented in this article.Address reprint requests to Babak J.
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.
The lymphatic system is fundamentally important to cardiovascular disease, infection and immunity, cancer, and probably obesity -the four major challenges in healthcare in the 21st century. This Review will consider the manner in which new knowledge of lymphatic genes and molecular mechanisms has demonstrated that lymphatic dysfunction should no longer be considered a passive bystander in disease but rather an active player in many pathological processes and, therefore, a genuine target for future therapeutic developments. The specific roles of the lymphatic system in edema, genetic aspects of primary lymphedema, infection (cellulitis/erysipelas), Crohn's disease, obesity, cancer, and cancer-related lymphedema are highlighted.
Acquired lymphedema is a cancer sequela and a global health problem currently lacking pharmacologic therapy. We have previously demonstrated that ketoprofen, an anti-inflammatory agent with dual 5-lipoxygenase and cyclooxygenase inhibitory properties, effectively reverses histopathology in experimental lymphedema. We show that the therapeutic benefit of ketoprofen is specifically attributable to its inhibition of the 5-lipoxygenase metabolite leukotriene B 4 (LTB 4 ). LTB 4 antagonism reversed edema, improved lymphatic function, and restored lymphatic architecture in the murine tail model of lymphedema. In vitro, LTB 4 was functionally bimodal: Lower LTB 4 concentrations promoted human lymphatic endothelial cell sprouting and growth, but higher concentrations inhibited lymphangiogenesis and induced apoptosis. During lymphedema progression, lymphatic fluid LTB 4 concentrations rose from initial prolymphangiogenic concentrations into an antilymphangiogenic range. LTB 4 biosynthesis was similarly elevated in lymphedema patients. Low concentrations of LTB 4 stimulated, whereas high concentrations of LTB 4 inhibited, vascular endothelial growth factor receptor 3 and Notch pathways in cultured human lymphatic endothelial cells. Lymphatic-specific Notch1 −/− mice were refractory to the beneficial effects of LTB 4 antagonism, suggesting that LTB 4 suppression of Notch signaling is an important mechanism in disease maintenance. In summary, we found that LTB 4 was harmful to lymphatic repair at the concentrations observed in established disease. Our findings suggest that LTB 4 is a promising drug target for the treatment of acquired lymphedema.
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