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How Diabetes Affects Lymphatic Vessels

Low levels of nitric oxide lead to leaky, porous lymphatic vessels…

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Lymphatic vessel leakage is associated with obesity, atherosclerosis, edema and cancer. Researchers at the University of Missouri have, for the first time, linked leaky lymphatic vessels to diabetes. Using mice as a model of type 2 diabetes, researcher Joshua Scallan and colleagues determined that the lymphatic vessels of diabetic mice were over 130 times more permeable than the vessels of the healthy mice.

“We now know for the first time that when individuals have type 2 diabetes, the walls of their lymphatic vessels are defective and become increasingly permeable, or leaky,” Scallan said. His team further hypothesized that since low levels of nitric oxide lead to dysfunction in the blood vasculature of type 2 diabetics; nitric oxide may play a role in lymphatic vasculature dysfunction as well. Supplementing the lymphatic tissue with L-arginine, the substrate for nitric oxide, resulted in improved vascular integrity in the lymph of the diabetic mice, but caused leakage in the lymph vessels of the healthy mice.

“Whether NO increases or decreases vascular permeability has been the subject of intense debate,” Scallan and his colleagues write. “Surprisingly, the idea that NO performs both roles in a context-dependent manner has never been tested. Here, we demonstrate that NO can increase the permeability of healthy lymphatic vessels and, using the same experimental preparation, can reduce lymphatic permeability once it is already elevated by disease.”

The researchers propose that the mechanism of vascular damage caused by reduced levels of NO is from its role in the inhibition of PDE3. PDE3 hydrolyzes cAMP, the molecule responsible for maintaining endothelial integrity. Low levels of NO fail to inhibit PDE3, and PDE3 is then activated by phosphorylation that occurs in high levels of insulin or leptin. “It is very likely that PDE3 not only requires release from inhibition, but also needs phosphorylation to be activated,” the researchers say. “High insulin or leptin levels, as occur in type 2 diabetes, are likely to be additional signals, and insulin has been reported to phosphorylate and activate PDE3 in multiple tissue types.”

The findings have significant meaning for those with type 2 diabetes, who are already at risk for the trappings of metabolic disease. “Based on an emerging body of literature, we expect that the degree of lymphatic barrier dysfunction in diabetic mice is sufficient to reduce lymph flow, thereby trapping lipids and cholesterol in the tissue,” the authors state. “This effect is likely significant, because inhibiting lymphatic transport of cholesterol bound to high-density lipoprotein from the tissues to the liver exacerbates atherosclerosis. Further, these findings link lymphatic endothelial dysfunction to lymph leakage, which leads to tissue adipose deposition, obesity, fibrosis, and inflammation.”

Further research is needed to determine if a drug like cilostazol, a PDE3 inhibitor currently FDA approved for the treatment of intermittent claudication, could restore lymphatic vessel integrity in type 2 diabetics, and reduce the risk atherosclerosis, dyslipidemia, and edema.

Practice Pearls:

  • Type 2 diabetics may have leaky lymphatic vessels, leading to obesity, dyslipidemia, atherosclerosis, and edema.
  • Dietary sources of L-arginine, such as meat and dairy products, may help reduce the permeability of lymphatic vessels.
  • Cilostazol and other PDE3 inhibitors may be used in the future to restore lymphatic vessel integrity.

Scallan JP, Hill MA, Davis MJ. “Lymphatic vascular integrity is disrupted in type 2 diabetes due to impaired nitric oxide signaling.” Cardiovascular Research. 1 Aug 2015. 107(3):89-97.