Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability

Blood. 2007 Apr 1;109(7):3088-98. doi: 10.1182/blood-2006-08-039438.


Pulmonary hypertension is a highly prevalent complication of sickle cell disease and is a strong risk factor for early mortality. However, the pathophysiologic mechanisms leading to pulmonary vasculopathy remain unclear. Transgenic mice provide opportunities for mechanistic studies of vascular pathophysiology in an animal model. By microcardiac catheterization, all mice expressing exclusively human sickle hemoglobin had pulmonary hypertension, profound pulmonary and systemic endothelial dysfunction, and vascular instability characterized by diminished responses to authentic nitric oxide (NO), NO donors, and endothelium-dependent vasodilators and enhanced responses to vasoconstrictors. However, endothelium-independent vasodilation in sickle mice was normal. Mechanisms of vasculopathy in sickle mice involve global dysregulation of the NO axis: impaired constitutive nitric oxide synthase activity (NOS) with loss of endothelial NOS (eNOS) dimerization, increased NO scavenging by plasma hemoglobin and superoxide, increased arginase activity, and depleted intravascular nitrite reserves. Light microscopy and computed tomography revealed no plexogenic arterial remodeling or thrombi/ emboli. Transplanting sickle marrow into wild-type mice conferred the same phenotype, and similar pathobiology was observed in a nonsickle mouse model of acute alloimmune hemolysis. Although the time course is shorter than typical pulmonary hypertension in human sickle cell disease, these results demonstrate that hemolytic anemia is sufficient to produce endothelial dysfunction and global dysregulation of NO.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anemia, Sickle Cell / blood*
  • Anemia, Sickle Cell / complications*
  • Anemia, Sickle Cell / genetics
  • Anemia, Sickle Cell / metabolism
  • Animals
  • Disease Models, Animal
  • Hemoglobin, Sickle / genetics
  • Hemolysis / physiology*
  • Humans
  • Hypertension, Pulmonary / etiology*
  • Hypertension, Pulmonary / metabolism*
  • Hypertension, Pulmonary / pathology
  • Hypertension, Pulmonary / physiopathology
  • Lung / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myocardium / pathology
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type II / metabolism
  • Nitric Oxide Synthase Type III
  • Transplantation Chimera
  • Vasodilation / drug effects
  • Vasodilation / physiology


  • Hemoglobin, Sickle
  • Nitric Oxide
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse