High-molecular-weight hyaluronan is a novel inhibitor of pulmonary vascular leakiness

Patrick A. Singleton, Tamara Mirzapoiazova, Yurong Guo, Saad Sammani, Nurbek Mambetsariev, Frances E. Lennon, Liliana Moreno-Vinasco, Joe G N Garcia

Research output: Contribution to journalArticlepeer-review

71 Scopus citations


Endothelial cell (EC) barrier dysfunction results in increased vascular permeability, a perturbation observed in inflammatory states, tumor angiogenesis, atherosclerosis, and both sepsis and acute lung injury. Therefore, agents that enhance EC barrier integrity have important therapeutic implications. We observed that binding of high-molecular-weight hyaluronan (HMW-HA) to its cognate receptor CD44 within caveolin-enriched microdomains (CEM) enhances human pulmonary EC barrier function. Immunocytochemical analysis indicated that HMW-HA promotes redistribution of a significant population of CEM to areas of cell-cell contact. Quantitative proteomic analysis of CEM isolated from human EC demonstrated HMW-HA-mediated recruitment of cytoskeletal regulatory proteins (annexin A2, protein S100-A10, and filamin A/B). Inhibition of CEM formation [caveolin-1 small interfering RNA (siRNA) and cholesterol depletion] or silencing (siRNA) of CD44, annexin A2, protein S100-A10, or filamin A/B expression abolished HMW-HA-induced actin cytoskeletal reorganization and EC barrier enhancement. To confirm our in vitro results in an in vivo model of inflammatory lung injury with vascular hyperpermeability, we observed that the protective effects of HMW-HA on LPS-induced pulmonary vascular leakiness were blocked in caveolin-1 knockout mice. Furthermore, targeted inhibition of CD44 expression in the mouse pulmonary vasculature significantly reduced HMW-HA-mediated protection from LPS-induced hyperpermeability. These data suggest that HMW-HA, via CD44-mediated CEM signaling events, represents a potentially useful therapeutic agent for syndromes of increased vascular permeability.

Original languageEnglish (US)
Pages (from-to)L639-L651
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Issue number5
StatePublished - Nov 2010


  • Acute lung injury
  • CD44
  • Vascular permeability

ASJC Scopus subject areas

  • Physiology (medical)
  • Physiology
  • Pulmonary and Respiratory Medicine
  • Cell Biology


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