Abstract
The glycosylated protein vasorin physically interacts with the transforming growth factor-beta1 (TGF-β1) and functionally attenuates its fibrogenic signaling in the vascular smooth muscle cells (VSMCs) of the arterial wall. Angiotensin II (Ang II) amplifies TGF-β1 activation in the VSMCs of the arterial wall with aging. In this study, we hypothesized that a reduced expression of the protein vasorin plays a contributory role in magnifying Ang II-associated fibrogenic signaling in the VSMCs of the arterial wall with aging. The current study shows that vasorin mRNA and protein expression were significantly decreased both in aortic wall and VSMCs from old (30 mo) vs. young (8 mo) FXBN rats. Exposing young VSMCs to Ang II reduced vasorin protein expression to the levels of old untreated cells while treating old VSMCs with the Ang II type AT1 receptor antagonist Losartan upregulated vasorin protein expression up to the levels of young. The physical interaction between vasorin and TGF-β1 was significantly decreased in old vs. young VSMCs. Further, exposing young VSMCs to Ang II increased the levels of matrix metalloproteinase type II (MMP-2) activation and TGF-β1 downstream molecules p-SMAD-2/3 and collagen type I production up to the levels of old untreated VSMCs, and these effects were substantially inhibited by overexpressing vasorin. Administration of Ang II to young rats (8 mo) for 28 days via an osmotic minipump markedly reduced the expression of vasorin. Importantly, vasorin protein was effectively cleaved by activated MMP-2 both in vitro and in vivo. Administration of the MMP inhibitor, PD 166793, for 6 mo to young adult (18 mo) via a daily gavage markedly increased levels of vasorin in the aortic wall. Thus, reduced vasorin amplifies Ang II profibrotic signaling via an activation of MMP-2 in VSMCs within the aging arterial wall.
Highlights
Collagen deposition and infiltration of medial vascular smooth muscle cells (VSMCs) into the intima are microscopic characteristics of arterial aging and angioplasty after injury [1,2,3]
Vasorin mRNA abundance was significantly decreased in cultured VSMCs isolated from old vs. young rat aortae (Figure 2A); likewise, vasorin immunostaining signal was diminished in old vs. young cells (Figure 2B); and vasorin protein levels determined by immunoblotting were significantly decreased in old vs. young rat VSMCs (Figure 2C)
The present study, for the first time, demonstrate that a reduction in the glycoprotein vasorin, coincides with the increases in Angiotensin II (Ang II) signaling, MMP-2 and TGF-β1 activation, in the arterial wall or VSMCs via AT1 signaling with advancing age (Figure 11)
Summary
Collagen deposition and infiltration of medial vascular smooth muscle cells (VSMCs) into the intima are microscopic characteristics of arterial aging and angioplasty after injury [1,2,3]. Consequent collagen buildup and intimal VSMCs cellularity result from increased angiotensin II (Ang II) signaling, activation of matrix metalloproteinase type II (MMP-2), and transforming growth factor-beta 1 (TGF-β1) in the aged arterial wall [4, 5]. The Ang II peptide and its receptor AT1 are upregulated in arterial walls with aging, and this phenomenon is closely associated with an enhancement of both sympathetic nerve activity and cyclic mechanical stress [1]. The ageassociated elevation of pulse pressure increases the arterial cyclic mechanical strain force and subsequently promotes the expression of both Ang II protein and AT1 receptor signaling [11,12,13]. Ang II is a potent activator of both TGF-β1 and MMP-2 [5]
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