Decreased arteriolar density in endothelial nitric oxide synthase knockout mice is due to hypertension, not to the constitutive defect in endothelial nitric oxide synthase enzyme

J Hypertens. 2002 Feb;20(2):273-80. doi: 10.1097/00004872-200202000-00017.

Abstract

Background: Hypertension in endothelial nitric oxide synthase knockout (eNOS-/-) mice is believed to be partly due to altered vasodilatation. However, nitric oxide (NO) is also known to play an important part in angiogenesis.

Objective: To investigate whether capillary and arteriolar density were impaired in eNOS-/- mice, as this could account for increased vascular resistance and hypertension.

Methods: Using immunohistochemistry with mouse monoclonal smooth muscle alpha-actin antibody to detect arterioles and rabbit polyclonal fibronectin antibody to detect capillaries, we quantified arteriolar and capillary density in the left ventricle and in the gracilis muscle from eNOS-/- mice compared with those in C57BL6J littermates (n = 6-8) in 8- and in 12-week-old mice. In a second set of experiments, we treated 8-week-old normotensive eNOS-/- mice with the antihypertensive vasodilator, hydralazine, for 1 month.

Results: Eight-week-old eNOS-/- mice were normotensive and presented similar arteriolar and capillary densities in cardiac and skeletal muscles compared with those in eNOS+/+ mice. Twelve-week-old eNOS/- mice were hypertensive (mean arterial pressure 118 +/- 21 mmHg compared with 64 +/- 2 mmHg; P < 0.05). Capillary densities were similar in eNOS-/- mice and eNOS+/+ mice in the heart (4154 +/- 123 and 4051 +/- 247/mm2, respectively) and in skeletal muscle (961 +/- 40 and 1025 +/- 41/mm2, respectively). Arteriolar densities were 15% lower in skeletal muscle and in the heart in eNOS-/- mice than in the eNOS+/+ control group (P < 0.05). Hydralazine prevented hypertension and arteriolar rarefaction in eNOS-/- mice, whereas capillary density was unaffected by treatment with the vasodilator.

Conclusion: In young non-hypertensive eNOS-/- mice, the lack of eNOS did not affect microvascular densities in either of the muscles studied. In adult hypertensive eNOS-/- mice, we observed a lower arteriolar density, but a similar capillary density compared with controls. Hydralazine prevented hypertension and arteriolar rarefaction in adult mice, suggesting a non-NO-dependent pathway. Capillary density was not affected by hydralazine.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antihypertensive Agents / therapeutic use
  • Arterioles / anatomy & histology
  • Arterioles / drug effects
  • Arterioles / enzymology*
  • Blood Pressure / drug effects
  • Blood Pressure / physiology
  • Body Weight / drug effects
  • Body Weight / physiology
  • Capillaries / anatomy & histology
  • Capillaries / drug effects
  • Capillaries / enzymology
  • Disease Models, Animal
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / enzymology*
  • Heart / anatomy & histology
  • Heart / drug effects
  • Heart / physiology
  • Hydralazine / therapeutic use
  • Hypertension / complications*
  • Hypertension / drug therapy
  • Hypertension / enzymology*
  • Male
  • Mice
  • Mice, Knockout / anatomy & histology*
  • Models, Cardiovascular
  • Muscle, Smooth, Vascular / blood supply*
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / enzymology*
  • Nitric Oxide Synthase / drug effects
  • Nitric Oxide Synthase / metabolism*
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Organ Size / drug effects
  • Organ Size / physiology

Substances

  • Antihypertensive Agents
  • Hydralazine
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse