Novel cardiovascular actions of the activins

Abstract

Proliferation and directed migration of vascular cells are key components in vascular diseases such as atherosclerosis and restenosis following percutaneous transluminal coronary angioplasty. However, the precise cellular and molecular mechanisms involved in the control of vascular cell proliferation or migration at the tissue level remain largely undefined. Molecules contributing to these processes are elaborated by distinct cell types and act in both autocrine and paracrine modes. They include two broad classes, polypeptide growth factors and vasoactive G-protein-coupled receptor (GPCR) agonists. Examples of the former, such as platelet-derived growth factor, bind to and activate cell surface receptor tyrosine kinases, initiating intracellular biochemical signaling pathways associated with cell proliferation or migration. In contrast, recent evidence suggests that vasoactive GPCR agonists (e.g. angiotensin II, endothelin-1, -thrombin) elicit cell growth indirectly by inducing the production of autocrine or paracrine factors in vascular cells. Recent studies have identified activin A as a novel component of conditioned medium obtained from GPCR agonist-stimulated vascular smooth muscle cells (SMCs). Although activin A alone only weakly stimulated rat aortic SMC DNA synthesis, it demonstrated a potent co-mitogenic effect in combination with either epidermal growth factor (EGF) or heparin binding EGF-like growth factor in these cells, increasing DNA synthesis by up to 5-and 4-fold respectively. Furthermore, in a rat carotid-injury model, activin A mRNA was upregulated within 6 h after injury, followed by increases in immunoreactive protein detected in the expanding neointima 7 to 14 days later. Taken together, these results indicate that activin A is a common vascular SMC-derived growth factor induced by vasoactive agonists that may, either alone or in combination with other factors, contribute to fibroproliferative vascular diseases.

Altered Transforming Growth Factor-Beta Signaling in a Murine Model of Thoracic Aortic Aneurysm

“…These ligands have been implicated in a wide array of functions, including embryonic development, differentiation, and bone formation, as well as elastin and type I collagen expression [23, 24]. Interestingly, the present study suggests that activin (composed of homo- or hetero- dimers of the inhibin βA- or βB- subunits) may be produced during aneurysm formation, which is consistent with a previous report demonstrating activin production in response to vascular injury and remodeling [25]. In addition, several ligand regulatory proteins also displayed elevated mRNA levels.…”

Sex differences in the renal transforming growth factor-β1 system after puberty

“…Activins and inhibins, peptide hormones that regulate gonadotropins [58], may affect the kidney on two levels. First, they may have direct effects on tissue to promote sclerosis via an autocrine or paracrine pathway [59][60][61][62]. Second, as members of the TGF-β superfamily, they utilize the same signalling pathway in the cell as TGF-β [38].…”

The role of inhibins and activins in prostate cancer pathogenesis.

“…The precise mediators of this process and their mechanisms of action remain to be delineated. Although activin has not been directly demonstrated to play a role in the mediation of angiogenesis, it is known that activin can stimulate the growth of vascular smooth muscle cells in rats and is up-regulated after vascular injury in the setting of atherosclerosis (Molloy et al 1999). There is strong induction of activin expression after skin injury and activin expression has been demonstrated in the repair processes of many tissues including skin, lung, intestine and the cardiovascular system.…”