No abstract

No abstract

Vascular smooth muscle cell (VSMC) dysfunction is a hallmark of small vessel disease, a common cause of stroke and dementia. Two of the most frequently mutated genes in familial small vessel disease are HTRA1 and NOTCH3. The protease HTRA1 cleaves the NOTCH3 ligand JAG1 implying a mechanistic link between HTRA1 and Notch signaling. Here we report that HTRA1 is essential for VSMC differentiation into the contractile phenotype. Mechanistically, loss of HTRA1 increased JAG1 protein levels and NOTCH3 signaling activity in VSMC. In addition, the loss of HTRA1 enhanced TGFβ-SMAD2/3 signaling activity. Activation of either NOTCH3 or TGFβ signaling resulted in increased transcription of the HES and HEY transcriptional repressors and promoted the contractile VSMC phenotype. However, their combined over-activation led to an additive accumulation of HES and HEY proteins, which repressed the expression of contractile VSMC marker genes. As a result, VSMC adopted an immature phenotype with impaired arterial vasoconstriction in Htra1-deficient mice. These data demonstrate an essential role of HTRA1 in vascular maturation and homeostasis by controlling Notch and TGFβ signaling.

Background and objectivesActive music-making in combination with physical exercise has evoked several positive effects in users of different age groups. These include enhanced mood, muscular effectivity, pain threshold, and decreased perceived exertion. The present study tested the applicability of this musical feedback system, called Jymmin®, in combination with strength-endurance exercises in a population of healthy older adults.Research design and methodsSixteen healthy, physically inactive older adults (5 males, 11 females) at the mean age of 70 years performed physical exercise in two conditions: A conventional work-out while listening passively music and a Jymmin® work-out, where musical sounds were created with one's work-out movements. According to the hypothesis that strength-endurance is increased during musical feedback exercise, parameters relating to strength-endurance were assessed, including exercise duration, number of repetitions, perceived exertion (RPE), and participants' mental state (Multidimensional Mood State Questionnaire; MDMQ).ResultsResults show that participants exercised significantly longer while doing Jymmin® (Mdn = 248.75 s) as compared to the conventional work-out (Mdn = 182.73 s), (Z = 3.408, p = 0.001). The RPE did not differ between conventional work-out and the Jymmin® condition, even though participants worked out significantly longer during the Jymmin® condition (Mdn = 14.50; Z = −0.905; p = 0.366). The results of the MDMQ showed no significant differences between both conditions (Z = −1.037; p = 0.300).Discussion and implicationsResults show that participants could work out longer while showing the same perceived exertion, relating to increased physical endurance. Music feedback work-out encouraged a greater degree of isometric contractions (muscle actively held at fixed length) and, therefore, less repetitions in this condition. In addition to the previously described effect on muscle effectivity, this non-stereotypic contraction pattern during music feedback training may have enhanced endurance in participants supporting them to better proportion energetic reserves during training (pacing).Clinical trial registrationIdentifier: DRKS00023645.