Mechanics and Function of the Pulmonary Vasculature: Implications for Pulmonary Vascular Disease and Right Ventricular Function

Lammers, Steven R.; Scott, Devon; Hunter, Kendall S.; Tan, Wei; Shandas, Robin; Stenmark, Kurt R.

doi:10.1002/cphy.c100070

Cited by 67 publications

(73 citation statements)

References 148 publications

(246 reference statements)

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“…However, more proximal remodeling in the larger pulmonary arteries may have a greater role in the pathogenesis of bovine pulmonary hypertension than previously appreciated. 14,27 Other, as yet unknown, risk factors may dictate the course of disease pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

An investigation into beef calf mortality on five high-altitude ranches that selected sires with low pulmonary arterial pressures for over 20 years

et al. 2013

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Producer reports from ranches over 2,438 meters in southwest Colorado suggest that the mortality of preweaned beef calves may be substantially higher than the national average despite the selection of low pulmonary pressure herd sires for over 20 years. Diagnostic investigations of this death loss problem have been limited due to the extensive mountainous terrain over which these calves are grazed with their dams. The objective of the current study was to determine the causes of calf mortality on 5 high-altitude ranches in Colorado that have been selectively breeding sires with low pulmonary pressure (<45 mmHg) for over 20 years. Calves were followed from branding (6 weeks of age) in the spring to weaning in the fall (7 months of age). Clinical signs were recorded, and blood samples were taken from sick calves. Postmortem examinations were performed, and select tissue samples were submitted for aerobic culture and/or histopathology. On the principal study ranch, 9.6% (59/612) of the calves that were branded in the spring either died or were presumed dead by weaning in the fall. In total, 28 necropsies were performed: 14 calves (50%) had lesions consistent with pulmonary hypertension and right-sided heart failure, and 14 calves (50%) died from bronchopneumonia. Remodeling of the pulmonary arterial system, indicative of pulmonary hypertension, was evident in the former and to varying degrees in the latter. There is a need to better characterize the additional risk factors that complicate pulmonary arterial pressure testing of herd sires as a strategy to control pulmonary hypertension.

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Section: Discussionmentioning

confidence: 99%

An investigation into beef calf mortality on five high-altitude ranches that selected sires with low pulmonary arterial pressures for over 20 years

et al. 2013

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“…These are transmitted to the microcirculation, where they might perpetuate or potentially even cause the microcirculatory changes, as well as contribute to the burden on the RV. 46 …”

Section: Vascular Remodeling Contributes To and Sustains The Chronic mentioning

confidence: 99%

Pathophysiology and Treatment of High-Altitude Pulmonary Vascular Disease

et al. 2015

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582I t is estimated that >140 million people live above 2500 m in various regions of the world.1 There are many challenges to living at high altitude, but chronic exposure to alveolar hypoxia is prominent among them. Inspired Po 2 falls from ≈150 mm Hg at sea level to ≈100 mm Hg at 3000 m and 43 mm Hg on the summit of Everest (8400 m). 2,3 The body responds by hyperventilating, increasing resting heart rate, and stimulating red cell production in an attempt to maintain the oxygen content of arterial blood at or above sea level values.2 However, hypoxic pulmonary vasoconstriction (HPV) and vascular remodeling, together with increased erythropoiesis, place an increased pressure load on the right ventricle (RV). How well healthy humans adapt to hypoxia depends on their rate of ascent to altitude, the severity and duration of their exposure, and their genetic background. Pathophysiology of Acclimatization to Hypoxia Pulmonary Vascular Response to HypoxiaFor most mammals, including humans, a rise in pulmonary artery pressure (PAP) is an early and inevitable consequence of ascent to high altitude. Resting mean PAP increases along a parabolic curve from 15 mm Hg at 2000 m to ≈30 mm Hg at 4500 m. 4 The exceptions and interindividual variation in the magnitude of response offer a natural experiment that might provide insight into fundamental underlying mechanisms (vide infra).The initial rise in PAP on exposure to hypoxia is attributed to HPV. With chronic hypoxia, other mechanisms that likely drive vascular remodeling soon contribute to the elevated pressure ( Figure 1A). After 2 or 3 weeks of hypoxia, there is little response to rebreathing 100% oxygen, indicating a structural resistance to pulmonary blood flow rather than one based solely on increased vasomotor tone. 6 A fall in PAP on re-exposure to a normal oxygen environment is evident in rats monitored by telemetry over days after removal from a hypoxic chamber 7 ( Figure 1B) and is also documented in humans. 4,8 Pulmonary Arteriolar Vasoconstriction Dominates the Acute Pulmonary Vascular Response to HypoxiaOxygen tension is a major regulator of pulmonary vascular tone and a physiological mechanism for matching perfusion with ventilation. A fall in alveolar Po 2 is the main stimulus for HPV, but a reduction in mixed venous and bronchial arterial Po 2 may also contribute. 9 Ventilation of intact lungs with a hypoxic gaseous mixture (eg, fraction of inspired oxygen=0.10) leads to acute pulmonary vasoconstriction throughout the pulmonary vascular bed, including nonmuscular arterioles, capillaries, and veins, but is most pronounced in small pulmonary arterioles. [10][11][12][13] That said, HPV is not distributed evenly throughout the lung and lung perfusion is inhomogeneous during hypoxia.14 HPV has at least 2 phases ( Figure 1A). An initial constrictor response that starts within seconds and reaches a maximum within minutes is followed by a sustained phase, which develops after 30 to 120 minutes. 9 A transient phase of vasodilation may be observed linking the two, an...

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“…Alterations of the vascular extracellular matrix (ECM) are increasingly being recognized as molecular drivers of PH. Dysregulated collagen and elastin production has been observed in both end-stage and early disease (1) and in both proximal and distal vessels (2). Pharmacologic targeting of vascular ECM can improve PH (3), but the processes that link ECM mechanotransduction (i.e., the processes that enable cells to sense and adapt to external mechanical forces) to the vasculature are just emerging.…”

Section: Introductionmentioning

confidence: 99%

Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension

Bertero¹,

Oldham²,

Cottrill³

et al. 2016

Journal of Clinical Investigation

316

338

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Mechanics and Function of the Pulmonary Vasculature: Implications for Pulmonary Vascular Disease and Right Ventricular Function

Cited by 67 publications

References 148 publications

An investigation into beef calf mortality on five high-altitude ranches that selected sires with low pulmonary arterial pressures for over 20 years

An investigation into beef calf mortality on five high-altitude ranches that selected sires with low pulmonary arterial pressures for over 20 years

Pathophysiology and Treatment of High-Altitude Pulmonary Vascular Disease

Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension

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