Published Online
on September 2, 2003

A more recent version of this article appeared on September 23, 2003

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Submitted on March 29, 2002
Revised on May 30, 2003
Accepted on June 3, 2003

Connective Tissue Growth Factor Is a Mediator of Angiotensin II-Induced Fibrosis

Mónica Rupérez BSc, Óscar Lorenzo PhD, Luis Miguel Blanco-Colio PhD, Vanesa Esteban BSc, Jesús Egido MD, and Marta Ruiz-Ortega PhD^*

From the Vascular and Renal Research Laboratory, Autónoma University, Fundación Jiménez Diaz, Universidad Autónoma, Madrid, Spain.

^* To whom correspondence should be addressed. E-mail: mruizo{at}fjd.es.

Background--Angiotensin II (Ang II) participates in the development of fibrosis during vascular damage. Connective tissue growth factor (CTGF) is a novel fibrotic mediator. However, the potential link between CTGF and Ang II has not been investigated.

Methods and Results--In vivo Ang II effects were studied by systemic infusion into normal rats to evaluate CTGF and extracellular matrix protein (ECM) expression by immunohistochemistry. In aorta of Ang II-infused rats, CTGF staining was markedly increased and ECM overexpression was observed. An AT₁ antagonist diminished CTGF and ECM. In growth-arrested vascular smooth muscle cells, Ang II induced CTGF mRNA expression after 1 hour, remained elevated up to 24 hours, and increased CTGF protein production, which was increased up to 72 hours. The AT₁ antagonist blocked Ang II-induced CTGF gene and protein expression. Early CTGF upregulation is independent of new protein synthesis. Several intracellular signals elicited by Ang II are involved in CTGF synthesis, including protein kinase C activation, reactive oxygen species, and transforming growth factor- endogenous production. Incubation with a CTGF antisense oligonucleotide decreased CTGF and fibronectin upregulation caused by Ang II.

Conclusions--Our results show that Ang II, via AT₁, increases CTGF in vascular cells both in vivo and in vitro. This novel finding suggests that CTGF may be a mediator of the profibrogenic effects of Ang II in vascular diseases.

Key words: angiotensin • muscle, smooth • cardiovascular diseases

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