Shear forces cause vessel identity crisis

By Eleanor McDermid

Lymphatic vessels exposed to fast-flowing blood take on characteristics associated with blood vessels, report researchers.

"An important implication of this study is that vessel identity remains plastic after vascular development is complete and may be radically altered by hemodynamic forces later in life," say Mark Kahn (University of Pennsylvania, Philadelphia, USA) and colleagues.

This means that, for example, shunting from the arterial to the pulmonary vasculature in congenital heart disease could trigger molecular changes in endothelial and vessel identity, they say.

"Defining these molecular changes is expected to provide new insight into the pathogenesis and treatment of human cardiovascular diseases such as vascular malformations."

The researchers studied mice lacking the SLP76 adaptor protein, which regulates blood and lymphatic vascular separation during embryonic development. These mice develop blood‑lymphatic vascular connections in the skin and intestine, yet early symptoms resolve, such as edema, and around one-third of the animals survive to adulthood.

The current study, published in the Journal of Clinical Investigation, shows that this resolution is caused by lymphatic vessels taking on the characteristics of blood vessels.

Lymphatic vessels in the mesentery of SLP76-deficient mouse neonates stained positive for lectin, showing that they were in contact with blood, but there were no blood-exposed mesenteric lymphatic vessels in adult SLP76-deficient mice. Adult mice also lacked large mesenteric vessels that were positive for the lymphatic endothelial marker LYVE1, despite the presence of mesenteric vascular bundles containing two thin-walled vessels suggestive of the congenital vein and lymphatic vessels.

These vascular bundles contained a large, thin-walled vessel ‑ in the anatomic position expected for the lymphatic vessel ‑ that stained positive for the vascular endothelial marker von Willebrand factor but was negative for the lymphatic endothelial markers LYVE1 and PROX1.

Further genetic studies in the mice showed that the lymphatic endothelial cells were reprogrammed into vascular endothelial cells, rather than being replaced by them.

This process did not occur in a different mouse model in which the animals have blood-filled mesenteric lymphatic vessels but very slow blood flow, indicating that exposure to blood per se did not trigger lymphatic vessel remodeling. The team conducted further experiments in isolated lymphatic endothelial cells, in which exposure to shear stress caused significant downregulation of lymphatic cell markers.

"These findings suggest that the genetic basis for human vascular malformations is only the first half of a story that is also written by the molecular and genetic responses to hemodynamic forces," say Kahn et al.

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