Linked mechanical and biological aspects of remodeling in mouse pulmonary arteries with hypoxia-induced hypertension

Abstract

Right heart failure due to pulmonary hypertension causes significant morbidity and mortality. To study the linked vascular mechanical and biological changes that are induced by pulmonary hypertension, we mechanically tested isolated left main pulmonary arteries from mice exposed to chronic hypobaric hypoxia and performed histological assays on contralateral vessels. In isolated vessel tests, hypoxic vessels stretched less in response to pressure than controls at all pressure levels. Given the short length and large diameter of the pulmonary artery, the tangent Young's modulus could not be measured; instead, an effective elastic modulus was calculated that increased significantly with hypoxia [(280 kPa (SD 53) and 296 kPa (SD 50) for 10 and 15 days, respectively, vs. 222 kPa (SD 35) for control; P < 0.02)]. Hypoxic vessels also had higher damping coefficients [(0.063 (SD 0.017) and 0.054 (SD 0.014) for 10 and 15 days, respectively, vs. 0.033 (SD 0.016) for control; P < 0.002)], indicating increased energy dissipation. The increased stiffness with hypoxia correlated with an increase in collagen thickness (percent collagen multiplied by wall thickness) as well as the sum of elastin and collagen thicknesses measured histologically in the artery wall. These results highlight the mechanobiological changes in the pulmonary vasculature that occur in response to hypoxia-induced pulmonary hypertension. Furthermore, they demonstrate significant vascular mechanical and biological changes that would increase pulmonary vascular impedance, leading to right heart failure.

Right coronary artery becomes stiffer with increase in elastin and collagen in right ventricular hypertrophy

“…3) for the intact artery ex vivo. The literature on the mechanical properties of isolated remodeled vessels is very limited (28). Those that do provide mechanical data focus only on distension with no regard to the axial stretch (28).…”

The role of collagen in extralobar pulmonary artery stiffening in response to hypoxia-induced pulmonary hypertension

“…Our laboratory has previously shown that HPH increases wave reflections in the mouse pulmonary circulation (44). Recent evidence showing that conduit PA stiffness is a strong predictor of mortality in PA hypertension (12, 30) further supports the importance of PA stiffness to pulmonary and right ventricular function.The dominant morphological changes in conduit PAs in response to HPH are accumulation of collagen and elastin (20, 21) and wall thickening (4,20,21,23). Stiffening of the extralobar PAs has been shown to be linked with accumulation of collagen and elastin (4,20,21,23,42).…”

“…biomechanics; mechanobiology; elastin; hydroxyproline; recovery HYPOXIC PULMONARY HYPERTENSION (HPH) is caused by living at high altitudes and is a complication of many lung diseases, including chronic obstructive pulmonary disease (1, 13, 16), cystic fibrosis (10), and obstructive sleep apnea (13), which contributes significantly to morbidity and mortality. Pulmonary vascular remodeling due to chronic HPH increases conduit pulmonary artery (PA) stiffness (4,20,21,23,34,42). Conduit PA stiffening likely increases wave reflections to impair right ventricular systolic function, much like aortic stiffening impairs left ventricular systolic function (18,29,33).…”

“…Pulmonary vascular remodeling due to chronic HPH increases conduit pulmonary artery (PA) stiffness (4,20,21,23,34,42). Conduit PA stiffening likely increases wave reflections to impair right ventricular systolic function, much like aortic stiffening impairs left ventricular systolic function (18,29,33).…”

“…Stiffening of the extralobar PAs has been shown to be linked with accumulation of collagen and elastin (4,20,21,23,42). Previous attempts to understand the individual roles of collagen and elastin in arterial mechanical function have focused on correlative relationships during HPH progression (20,21) or ex vivo degradation of one component before mechanical testing (23). A disadvantage of the first approach is that, if elastin also increases during HPH progression, the impact of either protein alone cannot be discerned; a disadvantage of the second approach is that degradation of one component may alter potentially important interactions between the two (9).…”