The Mechanobiology of Pulmonary Vascular Remodeling in the Congenital Absence of eNOS

Abstract

Primary pulmonary hypertension is a rare but deadly disease. Lungs extracted from PPH patients are deficient in endothelial nitric oxide synthase (eNOS), making the eNOS-null mouse a potentially useful model of the disease. To better understand the progression of pulmonary vascular remodeling in the congenital absence of eNOS, we induced pulmonary hypertension in eNOS-null mice using hypobaric hypoxia, and then quantified large artery structure and function in contralateral vessels. In particular, to assess structure we quantified diameter, wall thickness, and collagen, elastin and smooth muscle cell content; to quantify function we performed pressure-diameter tests. After remodeling, the pulmonary arteries had increased wall, collagen and elastin thicknesses compared to controls (P<0.05). The remodeled pulmonary arteries also had increased elastic moduli at low and high strains compared to controls (P<0.05). The increases in moduli at low and high strain correlated with increases in elastin and collagen thickness, respectively (P<0.05). These results provide insight into the mechanobiology of pulmonary vascular remodeling in the congenital absence of eNOS, and the coupled nature of these changes.

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).…”

“…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).…”

“…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).…”

“…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).…”