Chesler NC. The role of collagen in extralobar pulmonary artery stiffening in response to hypoxia-induced pulmonary hypertension. Am J Physiol Heart Circ Physiol 299: H1823-H1831, 2010. First published September 17, 2010 doi:10.1152/ajpheart.00493.2009.-Hypoxic pulmonary hypertension (HPH) causes extralobar pulmonary artery (PA) stiffening, which potentially impairs right ventricular systolic function. Changes in the extracellular matrix proteins collagen and elastin have been suggested to contribute to this arterial stiffening. We hypothesized that vascular collagen accumulation is a major cause of extralobar PA stiffening in HPH and tested our hypothesis with transgenic mice that synthesize collagen type I resistant to collagenase degradation (Col1a1 R/R ). These mice and littermate controls that have normal collagen degradation (Col1a1 ϩ/ϩ ) were exposed to hypoxia for 10 days; some were allowed to recover for 32 days. In vivo PA pressure and isolated PA mechanical properties and collagen and elastin content were measured for all groups. Vasoactive studies were also performed with U-46619, Y-27632, or calcium-and magnesium-free medium. Pulmonary hypertension occurred in both mouse strains due to chronic hypoxia and resolved with recovery. HPH caused significant PA mechanical changes in both mouse strains: circumferential stretch decreased, and mid-to-high-strain circumferential elastic modulus increased (P Ͻ 0.05 for both). Impaired collagen type I degradation prevented a return to baseline mechanical properties with recovery and, in fact, led to an increase in the low and mid-to-highstrain moduli compared with hypoxia (P Ͻ 0.05 for both). Significant changes in collagen content were found, which tended to follow changes in mid-to-high-strain elastic modulus. No significant changes in elastin content or vasoactivity were observed. Our results demonstrate that collagen content is important to extralobar PA stiffening caused by chronic hypoxia. 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). 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 ...

The recombinant congenic mouse strains HcB-8 and HcB-23 differ in femoral shape, size, and strength, with HcB-8 femora being more gracile, more cylindrical, weaker, and having higher Young's modulus. In previous work, we mapped a robust, pleiotropic quantitative trait locus for these bone traits. Ece1, encoding endothelin converting enzyme 1, is a positional candidate gene for this locus, and was less expressed in HcB-8 bone. We hypothesized that the same genetic factors would impose analogous developmental trajectories on arteries to those in bones. Cardiovascular hemodynamics and biomechanics of carotids were measured in adult HcB-8 and HcB-23 mice. Biological differences in heart and arteries were examined at mRNA and protein levels. As in bone, Ece1 expression was higher in HcB-23 heart and arteries (p < 0.05), and its expression was correlated with that of the endothelin B type receptor target Nos3, encoding endothelial nitric oxide synthase. HcB-8 mice had higher ambulatory blood pressure (p < 0.005) than HcB-23 mice. Ex vivo, at identical pressures, HcB-8 carotid arteries had smaller diameters and lower compliance (p < 0.05), but the same elastic modulus compared to HcB-23 carotid arteries. HcB-8 hearts were heavier than HcB-23 hearts (p < 0.01). HcB-8 has both small, stiff bones and small, stiff arteries, lower expression of Ece1 and Nos3, associated in each case with less favorable function. These findings suggest that endothelin signaling could serve as a nexus for the convergence of skeletal and vascular modeling, providing a potential mechanism for the epidemiologic association between skeletal fragility and atherosclerosis.

Our data suggest that an adaptation occurs in medial smooth muscle of atherosclerotic coronary artery to maintain distensibility of the vessel wall in the presence of endothelin-1. This may contribute to the vasospastic effect of locally increased endothelin-1 production that is reported in this condition.

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