Cyclic Strain and Hypertension Increase Osteopontin Expression in the Aorta

Abstract

Hypertension has a direct impact on vascular hypertrophy and is a known risk factor for the development of atherosclerosis. Osteopontin (OPN) has emerged as an important protein mediator of inflammation and remodeling of large arteries. However, its role and mechanism of regulation in the setting of hypertension is still unknown. Our objectives for this study were therefore to investigate the role of OPN in hypertension-induced vascular remodeling and inflammation. OPN Knockout (KO) and wild type (WT) mice were made hypertensive with angiotensin II (Ang II) infusion for seven days. We observed that OPN KO aortas were protected against Ang II-induced medial hypertrophy and inflammation, despite comparable increases in systolic blood pressure (SBP) in both groups. OPN expression was increased in WT aortas from hypertensive mice (induced by either Ang II or norepinephrine). OPN expression was increased in aortic smooth muscle cells (SMCs) subjected to cyclic mechanical strain suggesting that mechanical deformation of the aortic wall is responsible in part for the increased OPN expression induced by hypertension. Finally, we utilized hypertensive transgenic smooth muscle cell-specific catalase overexpressing (TgSMC-Cat) mice to determine the role of H2O2 in mediating hypertension-induced increases in OPN expression. We also found that the hypertension-induced increase in OPN expression was inhibited in transgenic smooth muscle cell-specific catalase overexpressing (TgSMC-Cat) mice, suggesting that H2O2, plays a vital role in mediating the hypertension-induced increase in OPN expression. Taken together, these results define a potentially important role for OPN in the pathophysiology of hypertension.

Rare Causes of Arterial Hypertension and Thoracic Aortic Aneurysms—A Case-Based Review

“…Hypertension results from the interaction of multiple genetic and environmental risk factors, most of them involved in the handling of salt and potassium [ 39 ]. Both mechanical and humoral factors are stimuli for subsequent SMC hypertrophy in this setting [ 40 ].…”

“…Osteopontin (OPN) (a proinflammatory, integrin-binding protein) characterizes the proliferating vascular SMC phenotype in the aneurysmal aortic wall and is also a prerequisite for vascular remodeling in hypertension [ 51 ]. OPN is regulated by cyclic mechanical strain and mediates neointimal formation and medial thickening [ 40 ]. Normally, increased PKG1 downregulates OPN to limit SMC migration (UniProt).…”

“…Normally, increased PKG1 downregulates OPN to limit SMC migration (UniProt). Nevertheless, oxidative stress in a hypertension setting may increase OPN [ 40 ].…”

The cofilin phosphatase slingshot homolog 1 restrains angiotensin II-induced vascular hypertrophy and fibrosis in vivo

“…This switch is associated with increased proliferation and production of extracellular matrix proteins (60, 61). Interestingly, the multifunctional protein OPN and the extracellular matrix protein FN1 are induced in vascular smooth muscle cells in response to stretch and Ang II stimulation (12, 13, 60, 62–65). Here we demonstrate that Ssh1 −/− mice have increased Opn and Fn1 mRNA expression basally when compared to wild type littermates and that the loss of SSH1 further potentiates the Ang II-dependent increase in aortic Opn and Fn1 mRNA.…”

Vascular Extracellular Matrix Remodeling and Hypertension

“…The N-terminal OPN fragment, a product of OPN proteolysis by thrombin and MMPs, correlates with increased inflammation severity in carotid plaques in patients with hypertension (2). The involvement of OPN in hypertension-related inflammation and remodeling is further evidenced by the finding that the early macrophage infiltration into the arterial wall in response to hypertension is blunted in OPN-deficient mice (22).…”