Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis

Abstract

Lymphatic vessels are essential for the removal of interstitial fluid and prevention of tissue edema. Lymphatic capillaries lack associated mural cells, and collecting lymphatic vessels have valves, which prevent lymph backflow. In lymphedema-distichiasis (LD), lymphatic vessel function fails because of mutations affecting the forkhead transcription factor FOXC2. We report that Foxc2(-/-) mice show abnormal lymphatic vascular patterning, increased pericyte investment of lymphatic vessels, agenesis of valves and lymphatic dysfunction. In addition, an abnormally large proportion of skin lymphatic vessels was covered with smooth muscle cells in individuals with LD and in mice heterozygous for Foxc2 and for the gene encoding lymphatic endothelial receptor, Vegfr3 (also known as Flt4). Our data show that Foxc2 is essential for the morphogenesis of lymphatic valves and the establishment of a pericyte-free lymphatic capillary network and that it cooperates with Vegfr3 in the latter process. Our results indicate that an abnormal interaction between the lymphatic endothelial cells and pericytes, as well as valve defects, underlie the pathogenesis of LD.

Abnormal Shh and FOXC2 expression correlates with aberrant lymphatic development in human fetuses with increased nuchal translucency

“…Besides the altered endothelial differentiation found in the lymphatic endothelial cells, smooth muscle cells (SMCs) surrounded the JLS which normally only line arteries, veins and large collecting lymph vessels (Petrova et al, 2004;Bekker et al, 2006a). Interestingly, previous research in Foxc2 −/− mice also showed an abnormal amount of SMCs surrounding enlarged lymph vessels (Petrova et al, 2004).…”

Developmental and pathological lymphangiogenesis: from models to human disease

“…This factor is highly expressed in the developing lymphatic vasculature and in the luminal valves in adult lymphatic vessels (Dagenais et al 2004;Petrova et al 2004). Initial development of the lymphatic vasculature proceeds normally in the absence of FOXC2; however, later the patterning of the lymphatic vasculature becomes abnormal.…”

“…The human disease lymphedema-distichiasis (LD), an autosomal dominant disease, is caused by heterozygousloss-of-function mutations of Foxc2 (Fang et al 2000). Unlike in congenital lymphedema, the lymphatic vasculature in LD is normal or hyperplastic, but there is lymph backXow, presumably due to abnormal lymphatic valves, defective patterning and the presence of ectopic SMCs (Brice et al 2002;Petrova et al 2004). Interestingly, a recent study showed that Foxc2 mutations are associated with primary venous valve failure in both the superWcial and deep veins in the lower limb.…”

“…LD is associated with abnormal lymph vessel patterning, agenesis of lymphatic valves, and abnormal recruitment of SMCs . Generated Foxc2 § and Foxc2 ¡/¡ mice constitute useful animal models for this disorder (Kriederman et al 2003;Petrova et al 2004). A recent study reported renal disease and diabetes mellitus in combination with LD caused by a Foxc2 mutation, reXecting the developmental role of FOXC2 in multiple tissues (YildirimToruner et al 2004).…”

Le système vasculaire lymphatique : états des connaissances et implications dermatologiques potentielles

“…Une mutation du gène FOXC2 (16q24), facteur de transcription responsable de la formation des valves et de l'inhibition du recrutement des cellules musculaires lisses ou des péricytes autour des vaisseaux lymphatiques, a été mise en évidence dans cette pathologie. Des manipulations génétiques chez la souris ont confirmé l'effet de cette mutation sur le phénotype [16].…”