Expression of the bumetanide-sensitive Na-K-Cl cotransporter BSC2 is differentially regulated by fluid mechanical and inflammatory cytokine stimuli in vascular endothelium.

In vascular endothelium, the electroneutral Na-K-Cl cotransport system is thought to function in the maintenance of a selective permeability barrier in certain vascular beds (e.g., brain), as well as in the preservation of endothelial homeostasis in the face of fluctuating osmotic conditions that may accompany certain pathophysiological conditions (e.g., diabetes mellitus). Here we demonstrate that the gene encoding the bumetanide-sensitive cotransporter BSC2, one of the two major isoforms of Na-K-Cl cotransporters present in mammalian cells, can be differentially regulated by inflammatory cytokines and fluid mechanical forces in cultured endothelium. Interleukin-1beta and tumor necrosis factor-alpha significantly upregulate expression of BSC2 mRNA and protein in human umbilical vein endothelial cells, a response that is inhibited by pretreatment with interferon-gamma. Steady laminar fluid shear stress, at a physiologic magnitude (10 dyn/cm2), is also able to induce and maintain elevated expression of BSC2 in cultured human umbilical vein endothelial cells, while a comparable time-averaged magnitude of turbulent fluid shear stress is not. In vivo, BSC2 mRNA is upregulated after intraperitoneal administration of bacterial endotoxin (LPS) in murine lung and kidney, but not in cardiac tissue. These results provide the first experimental evidence that the BSC2 gene can be selectively regulated by different inflammatory cytokine and fluid mechanical stimuli in endothelium, and support a role for BSC2 in vascular homeostasis and inflammation.

Capillary hypertension and abnormal pressure dynamics in patients with essential hypertension.

1. Pressure was measured within 28 capillaries of the nailfolds of nine patients with essential hypertension and in 33 capillaries of nine age- and sex-matched normotensive control subjects, using direct micropuncture, a dynamic servo-nulling system and computerized analysis. 2. Average pressure at the apex of the capillary was found to be elevated in the patients with hypertension (21.1 +/- 4.9 mmHg compared with 13.0 +/- 2.0 mmHg in the control subjects; mean +/- SD, P less than 0.01). If the two groups were combined, there was an overall correlation between average capillary pressure and mean blood pressure (r = 0.68, P less than 0.01, n = 18), but within each group separately there was no significant relation between these parameters. 3. There were also abnormalities in the waveforms of pulsations in capillary pressure in the group with hypertension, with an increased attenuation of high-frequency harmonics. Pulses appeared to be conducted more rapidly along the vascular tree in the patients with hypertension. 4. The elevation of capillary pressure in essential hypertension demonstrated in this study is in agreement with indirect evidence of capillary hyperfiltration provided by other studies which showed a reduced plasma volume and increased transcapillary escape rate of plasma proteins. 5. The finding of elevated capillary pressure demands the inclusion of the postcapillary segment (and possibly vascular density) in the resistance equation in essential hypertension.