Background-Smoothelins are actin-binding proteins that are abundantly expressed in healthy visceral (smoothelin-A) and vascular (smoothelin-B) smooth muscle. Their expression is strongly associated with the contractile phenotype of smooth muscle cells. Analysis of mice lacking both smoothelins (Smtn-A/B Ϫ/Ϫ mice) previously revealed a critical role for smoothelin-A in intestinal smooth muscle contraction. Here, we report on the generation and cardiovascular phenotype of mice lacking only smoothelin-B (Smtn-B Ϫ/Ϫ ). Methods and Results-Myograph studies revealed that the contractile capacity of the saphenous and femoral arteries was strongly reduced in Smtn-B Ϫ/Ϫ mice, regardless of the contractile agonist used to trigger contraction. Arteries from Smtn-A/B Ϫ/Ϫ compound mutant mice exhibited a similar contractile deficit. Smtn-B Ϫ/Ϫ arteries had a normal architecture and expressed normal levels of other smooth muscle cell-specific genes, including smooth muscle myosin heavy chain, ␣-smooth muscle actin, and smooth muscle-calponin. Decreased contractility of Smtn-B Ϫ/Ϫ arteries was paradoxically accompanied by increased mean arterial pressure (20 mm Hg) and concomitant cardiac hypertrophy despite normal parasympathetic and sympathetic tone in Smtn-B Ϫ/Ϫ mice. Magnetic resonance imaging experiments revealed that cardiac function was not changed, whereas distension of the proximal aorta during the cardiac cycle was increased in Smtn-B Ϫ/Ϫ mice. However, isobaric pulse wave velocity and pulse pressure measurements indicated normal aortic distensibility. Key Words: hypertension Ⅲ hypertrophy Ⅲ muscle contraction Ⅲ muscle, smooth Ⅲ vascular resistance H ypertension is a common condition in Western countries, affecting Ϸ27% of the population worldwide. It is a major risk factor for the development of life-threatening conditions such as coronary heart disease and stroke. However, the cause of increased blood pressure is unknown in most patients. 1 Smooth muscle contractility is one of the primary determinants of vascular resistance, thereby contributing significantly to the maintenance of a physiological blood pressure. Accordingly, molecular defects in the regulation or mechanics of arterial smooth muscle contraction generally cause profound cardiovascular phenotypes. For example, ␣-smooth muscle actin (␣-SMA) knockout mice display impaired vascular contractility and reduced blood flow. 2 Likewise, smooth muscle myosin heavy chain (SM-MHC)-B knockouts show a significant decrease in maximal shortening velocity of vascular smooth muscle, 3 and SM-calponin-deficient mice have impaired mean arterial pressure (MAP) regulation. 4 Clinical Perspective p 836Despite the importance of smooth muscle cell (SMC) contraction for the cardiovascular system, the contractile process itself is still incompletely understood. In particular, the functions of regulatory proteins that are connected to the actin-myosin filaments in vascular SMCs remain poorly defined. 5 Candidate thin filament regulatory proteins that have not been studied in th...

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