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 GN Garcia

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

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)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume299
Issue number5
DOIs
StatePublished - Nov 2010
Externally publishedYes

Fingerprint

Hyaluronic Acid
Caveolins
Blood Vessels
Filamins
Molecular Weight
Lung
Endothelial Cells
Annexin A2
Caveolin 1
S100 Proteins
antineoplaston A10
Capillary Permeability
Small Interfering RNA
Cytoskeletal Proteins
Acute Lung Injury
Lung Injury
Knockout Mice
Proteomics
Actins
Sepsis

Keywords

  • Acute lung injury
  • CD44
  • Vascular permeability

ASJC Scopus subject areas

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

Cite this

High-molecular-weight hyaluronan is a novel inhibitor of pulmonary vascular leakiness. / Singleton, Patrick A.; Mirzapoiazova, Tamara; Guo, Yurong; Sammani, Saad; Mambetsariev, Nurbek; Lennon, Frances E.; Moreno-Vinasco, Liliana; Garcia, Joe GN.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 299, No. 5, 11.2010.

Research output: Contribution to journalArticle

Singleton, Patrick A. ; Mirzapoiazova, Tamara ; Guo, Yurong ; Sammani, Saad ; Mambetsariev, Nurbek ; Lennon, Frances E. ; Moreno-Vinasco, Liliana ; Garcia, Joe GN. / High-molecular-weight hyaluronan is a novel inhibitor of pulmonary vascular leakiness. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2010 ; Vol. 299, No. 5.
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