Conditional and targeted overexpression of vascular chymase causes hypertension in transgenic mice

We cloned a rat vascular chymase (RVCH) from smooth muscle cells (SMCs) tha t converts angiotensin I to II and is up-regulated in SMC from spontaneousl y hypertensive vs, normotensive rats. To determine whether increased activi ty of RVCH is sufficient to cause hypertension, transgenic mice were genera ted with targeted conditional expression of RVCH to SMC, with the use of th e tetracycline-controlled transactivator (tTA). We confirmed conditional ex pression of RVCH by mRNA, protein, and chymase activity in the absence, but not in the presence, of dietary doxycycline. The systolic blood pressure ( mmHg), measured by carotid artery cannulation at 10-12 weeks of age, was hi gher in tTA+/RVCH + mice than in nonbinary transgenic littermates (136 +/- 4 vs. 109 +/- 3) (P < 0.05), as were the diastolic and mean pressures. Hype rtension was completely reversed by doxycycline, suggesting a causal link w ith chymase expression. Medial thickening of mesenteric arteries from tTA+/ RVCH+ mice vs. littermates (0.82 +/- 0.1 vs. 0.42 +/- 0.02) (P < 0.05) was associated with increased SMC proliferation, as judged by positive immunore activity, with the use of an antibody to the proliferating cell nuclear ant igen. These structural changes were prevented by doxycycline. Perfusion myo graphy of mesenteric arteries from tTA+/RVCH+ mice also revealed increased vasoconstriction in response to phenylephrine and impaired metacholine-indu ced vasodilatation when compared with littermate controls or with the doxyc yline-treated group. Our studies suggest that up-regulation of this vascula r chymase is sufficient to cause a hypertensive arteriopathy, and that RVCH may be a candidate gene and a therapeutic target in patients with high blo od pressure.