Research Article: Spatiotemporal Dysfunction of the Vascular Permeability Barrier in Transgenic Mice with Sickle Cell Disease

Date Published: June 12, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Samit Ghosh, Fang Tan, Solomon F. Ofori-Acquah.


Sickle cell disease (SCD) is characterized by chronic intravascular hemolysis that generates excess cell-free hemoglobin in the blood circulation. Hemoglobin causes multiple endothelial dysfunctions including increased vascular permeability, impaired reactivity to vasoactive agonists, and increased adhesion of leukocytes to the endothelium. While the adhesive and vasomotor defects of SCD associated with cell-free hemoglobin are well defined, the vascular permeability phenotype remains poorly appreciated. We addressed this issue in two widely used and clinically relevant mouse models of SCD. We discovered that the endothelial barrier is normal in most organs in the young but deteriorates with aging particularly in the lung. Indeed, middle-aged sickle mice developed pulmonary edema revealing for the first time similarities in the chronic permeability phenotypes of the lung in mice and humans with SCD. Intravenous administration of lysed red blood cells into the circulation of sickle mice increased vascular permeability significantly in the lung without impacting permeability in other organs. Thus, increased vascular permeability is an endothelial dysfunction of SCD with the barrier in the lung likely the most vulnerable to acute inflammation.

Partial Text

Sickle cell disease (SCD) is characterized by the production of red blood cells with increased propensity for lysis and adhesion [1]. Its clinical manifestations fall broadly into two subphenotypes defined by hyperhemolysis and vasoocclusion [2]. At least 30% of the hemolysis in SCD is intravascular [3], which means that the endothelial wall in this disease is persistently exposed to cell-free hemoglobin. The endothelium is a semipermeable barrier that regulates the response of the vascular wall to inflammatory agonists. This response involves activation of adhesion molecule expression, increased permeability of the endothelium, and extravasations of fluid from the blood into interstitial tissue compartments [4]. Increased vascular permeability results from opening of gaps at sites of endothelial cell-cell contacts. There are multiple indicators of systemic inflammation in SCD [5]. In addition, markers of vascular inflammation have also been documented [6–8]. There is increased expression of adhesion molecules in the pulmonary endothelium of the Berkeley sickle mice [9], although the histology of these same mice shows less severe inflammatory and ischemic changes and no evidence of pneumonia [10]. Nonetheless, they spontaneously develop pulmonary hypertension [11], which is a major problem in SCD [12]. Pulmonary edema and the acute chest syndrome implicate increased vascular permeability in both chronic and acute complications of SCD [13, 14]. Despite this significance, there is currently no knowledge of the vascular permeability phenotypes of major organs that are impacted by SCD.

In SCD, the adhesive and vasomotor defects of the vasculature are well defined [17–20], while the vascular permeability remains poorly appreciated. To address this knowledge gap, adult (3–6 months) and middle-aged (10–13 months) mice were injected with 1% Evans blue via the tail vein and the amount of dye that leaked from the circulation into the parenchyma of individual organs examined. Figure 1(a) shows virtually no leakage in the brain contrary to the clear evidence of endothelial barrier breakdown in the other organs. Quantification of vascular leakage revealed that the endothelial barrier is generally more permeable in the sickle mice than in control littermates (Figures 1(b) and 1(c)), despite some differences in the two transgenic models. Indeed, there was a significant correlation between steady-state hemoglobin concentration and lung permeability (Figure 1(d)) (r = −0.7639, P < 0.0001), indicating that endothelial barrier dysfunction is related to an aspect of SCD. Unlike most organs, vascular permeability in the lung in middle-aged sickle mice was significantly higher than in adult mice, highlighting a role for age in this disease process. This was investigated by extending our study to include younger mice aged 5-6 weeks. Remarkably, permeability in the heart and lung at this early stage of the disease was identical to that of the brain, which is widely known to have a highly restrictive barrier (Figures 1(e) and 1(f)). Thus, the endothelial barrier in SCD is normal in most organs in the young, becomes abnormal during adulthood, and deteriorates further with aging particularly in the lung.   Source:


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