ANGIOTENSIN-II INCREASES VASCULAR-PERMEABILITY FACTOR GENE-EXPRESSIONBY HUMAN VASCULAR SMOOTH-MUSCLE CELLS

Angiotensin II (Ang II) has been implicated in the pathogenesis of the vascular injury associated with hypertension and diabetes mellitus. I ncreased vascular permeability is an important early manifestation of endothelial dysfunction and the pathogenesis of atherosclerosis. How A ng II contributes to endothelial dysfunction and promotes an increase in vascular permeability is unknown but is classically attributed to i ts presser actions. We demonstrate that human vascular smooth muscle c ells express abundant mRNA for vascular permeability/endothelial growt h factor. Vascular permeability factor is a 34- to 42-kD glycoprotein that markedly increases vascular endothelial permeability and is a pot ent endothelial mitogen. Ang II potently induced a concentration-depen dent (maximal, 10(-7) mol/L) and time-dependent increase in vascular p ermeability factor mRNA expression by human vascular smooth muscle cel ls that was maximal after 3 hours and diminished by 24 hours. Ang II-i nduced vascular permeability factor mRNA expression by human vascular smooth muscle cells was inhibited by the specific Ang II receptor anta gonist losartan (DuP 753), confirming that this is an Ang II receptor subtype 1-mediated event. These results describe a new action of Ang I I on human vascular smooth muscle, notably the induction of vascular p ermeability factor mRNA expression. The wide spectrum and potent activ ity of vascular permeability factor suggest a novel mechanism whereby Ang II could locally and directly influence the permeability, growth, and function of the vascular endothelium independent of changes in hem odynamics.