Endothelial Dysfunction and Paradoxical Resistance to Thrombosis in a Transgenic Mouse Model of Severe Hyperhomocysteinemia.

Hyperhomocysteinemia induced by low folate or high methionine diets produces endothelial dysfunction and accelerated thrombosis in mice, but it is not known if these vascular effects are influenced by homocysteine-independent effects of dietary perturbation. To determine the vascular phenotype of severe hyperhomocysteinemia in the absence of dietary intervention, we utilized a recently developed transgenic mouse model of cystathionine β-synthase (CBS) deficiency. In this model, the early lethality of homozygous Cbs-deficient mice (Cbs-/-) is rescued by a zinc-inducible human CBSI278T (hCBS-I278T) transgene under the control of a metallotheinein promoter. The I278T mutation is a common CBS mutation found in human patients with homocystinuria. We bred Cbs+/− male to Cbs+/− hCBS-I278T female mice. The mothers were given drinking water supplemented with 25 mmol/L zinc sulfate. Pups were weaned at 4–5 weeks of age and did not receive supplemental zinc after weaning. At 20 weeks of age, plasma total homocysteine was significantly higher in Cbs-/- hCBS-I278T mice (350±17 μmol/L) compared with Cbs+/+ hCBS-I278T (8.0±0.6 μmol/L) or wild-type Cbs+/+ (7.2±0.8 μmol/L) littermates (P<0.001). Maximal dilatation of pial arterioles to the endotheliumdependent dilator, acetylcholine, was decreased significantly in Cbs-/- CBS-I278T mice (10±2 %) compared with Cbs+/+ hCBS-I278T (25±2 %) mice (P<0.001). Dilatation responses to the endothelium-independent vasodilator, nitroprusside, were similar in both groups. Surprisingly, the time to stable occlusion after photochemical injury (rose bengal and green laser) of the carotid artery was significantly delayed in Cbs-/- hCBSI278T mice (71±10 minutes) compared with Cbs+/+ hCBS-I278T (30±10 minutes) or Cbs+/+ mice (33±8 minutes) (P<0.05). The tail bleeding time was comparable in all 3 groups. We conclude that severe hyperhomocysteinemia due to genetic deficiency of Cbs produces endothelial dysfunction but not accelerated thrombosis in the absence of dietary intervention in mice.