Acute aortic dissection (AAD) is caused by the disruption of intimomedial layer of the aortic walls, which is immediately life-threatening. Although recent studies indicate the importance of proinflammatory response in pathogenesis of AAD, the mechanism to keep the destructive inflammatory response in check is unknown. Here, we report that induction of tenascin-C (TNC) is a stress-evoked protective mechanism against the acute hemodynamic and humoral stress in aorta. Periaortic application of CaCl2 caused stiffening of abdominal aorta, which augmented the hemodynamic stress and TNC induction in suprarenal aorta by angiotensin II infusion. Deletion of Tnc gene rendered mice susceptible to AAD development upon the aortic stress, which was accompanied by impaired TGFβ signaling, insufficient induction of extracellular matrix proteins and exaggerated proinflammatory response. Thus, TNC works as a stress-evoked molecular damper to maintain the aortic integrity under the acute stress.