Mitochondria DNA mutations cause sex-dependent development of hypertension and alterations in cardiovascular function

Abstract

Aging is associated with conduit artery stiffening that is a risk factor for and can precede hypertension and ventricular dysfunction. Increases in mitochondria DNA (mtDNA) frequency have been correlated with aging. Mice with a mutation in the encoding domain (D257A) of a proof-reading deficient version of mtDNA polymerase-γ (POLG) have musculoskeletal features of premature aging and a shortened lifespan. However, few studies using these mice have investigated the effects of mtDNA mutations on cardiovascular function. We hypothesized that the proof-reading deficient mtDNA POLG leads to arterial stiffening, hypertension, and ventricular hypertrophy. Ten to twelve month-old D257A mice (n=13) and age- and sex-matched wild-type controls (n=13) were catheterized for hemodynamic and ventricular function measurements. Left common carotid arteries (LCCA) were harvested for mechanical tests followed by histology. Male D257A mice had pulmonary and systemic hypertension, arterial stiffening, larger LCCA diameter (701 ± 45 vs. 597 ± 60 μm), shorter LCCA axial length (8.96 ± 0.56 vs. 10.10 ± 0.80 mm), and reduced hematocrit (29.1 ± 6.1 vs. 41.3 ± 8.1; all p<0.05). Male and female D257A mice had biventricular hypertrophy (p<0.05). Female D257A mice did not have significant increases in pressure or arterial stiffening, suggesting that the mechanisms of hypertension or arterial stiffening from mtDNA mutations differ based on sex. Our results lend insight into the mechanisms of age-related cardiovascular disease and may point to novel treatment strategies to address cardiovascular mortality in the elderly.

Pulmonary arterial strain- and remodeling-induced stiffening are differentiated in a chronic model of pulmonary hypertension

“…Wall thickness was determined using measurements from at least three representative fields of view (FOV). The area containing collagen or elastin was determined by color thresholding in a representative FOV by an observer blinded to the experimental condition as done previously in our lab (Golob et al, 2015; Wang et al, 2013b). Collagen and elastin area percentages were calculated by dividing the area marked positive for the ECM proteins by the total tissue area.…”

Stretch calculated from grip distance accurately approximates mid-specimen stretch in large elastic arteries in uniaxial tensile tests

“…Understanding the changes in arterial mechanical properties during cardiovascular disease progression is useful for prognoses and monitoring therapeutic efficacy. Several ex vivo mechanical tests have been used to characterize the mechanical properties of large elastic arteries including uniaxial and biaxial tests, and pressure inflation-force test (Holzapfel, 2006; Kao et al, 2011; Lammers et al, 2008; Sommer et al, 2010; Golob et al, 2015). The uniaxial test is performed with an apparatus that applies a tensile force to a rectangular strip in only one direction.…”

Cardiovascular Function and Structure are Preserved Despite Induced Ablation of BMP1-Related Proteinases

“…The descending thoracic aortas (DTA) were harvested and tested using a modified version of the isolated vessel mechanical testing system previously used in our group 21, 28, 52 . To measure axial force during vessel extension, a force transducer (400A, Aurora Scientific) was added to the system and affixed to a 3-stage micrometer (Parker, Hannifin Corporation, Mayfield Heights, OH) for three dimensional control of the distal cannula.…”

“…Static extension testing for the axial direction was then performed at 90 mmHg by measuring axial force (F) at multiple axial stretch values in increments of 0.1. Finally, dynamic testing was performed at λ iv to quantify viscoelastic properties at physiologically relevant frequencies as done previously 21, 52 . Sinusoidal pressure waveforms from 90–120 mmHg at 1, 5, and 10 Hz were applied to each vessel.…”