My research has focused on understanding the role of endothelial glycocalyx, a molecular layer composed of glycoproteins and proteoglycans found on the surface of vascular endothelial cells. The glycocalyx and has been hypothesized to be an important component of the vascular barrier that determines capillary permeability.
In 1998, the Nobel Prize in Medicine was awarded to Robert F. Furchgott, Louise J. Ignarroa and
Ferid Murad for their work in identifying endothelial-derived relaxing factor (EDRF) as nitric
oxide (see: https://www.nobelprize.org/prizes/medicine/1998/press-release ). How increased
blood flow lead to nitric oxide release was unknown but hundreds of scientists around the
world were working to identify a flow-sensor on endothelial cells.
In the early 2000’s, my collaborators and I discovered that heparan sulfate proteoglycans
(HSPG), a major component of the endothelial glycocalyx, modulates flow-dependent nitric
oxide production in arterial endothelial cells. Our paper (Florian J et al Circ Res. link ) was the
first paper to describe HSPG as an arterial endothelial flow-sensor that modulated nitric oxide
production. This landmark study ushered in huge increase in the glycocalyx and endothelial
mechano-biology. In subsequent follow-up studies, my laboratory has demonstrated that HSPG
have a similar function in lung capillaries and play an important role in lung fluid balance,
especially during acute heart failure.
These findings have important implications in the treatment of acute heart failure and
hypertensive heart failure. When a patient has a heart attack and the heart can’t pump blood
effectively, blood pressure in the lung capillaries increase and this causes acute pulmonary
edema, one of the primary symptoms of heart failure. When we blocked nitric oxide
production prior to inducing acute heart failure, we observed that subjects did not develop
pulmonary edema and the amount of oxygen in the blood did not change. Therefore, increased
pressure alone is insufficient to cuase pulmonary edema and active signaling by endothelial
cells, by production of nitric oxide, leads to barrier failure and pulmonary edema.
These findings should change how we think of treating pulmonary edema. To this end, my
laboratory has developed novel therapeutic polymers that bind to and alter the biomechanics
of the glycocalyx and prevent pressure-induced pulmonary edema. These prototype polymers
serve as proof-in-concept for developing novel heart failure therapies.
Please review my publications and review articles that cover my work in greater detail.