The Mechanobiology of Vascular Remodeling in the Aging Lung

Abstract

Aging is accompanied by declining lung function and increasing susceptibility to lung diseases. The role of endothelial dysfunction and vascular remodeling in these changes is supported by growing evidence, but underlying mechanisms remain elusive. In this review we summarize functional, structural, and molecular changes in the aging pulmonary vasculature and explore how interacting aging and mechanobiological cues may drive progressive vascular remodeling in the lungs.

Keywords: matrix; pulmonary; senescence; stiffness; vessel.

FIGURE 1.

Pathophysiological features and assessment modalities for vascular remodeling in the pulmonary arterial tree This schematic of the pulmonary arterial system illustrates its branching structure, featuring large-diameter elastic arteries, smaller muscular arteries and arterioles, and extensive microcirculation. Unlike in the systemic circulation, the high compliance of the pulmonary arterial tree distributes across the entire vascular bed, contributing to impedance of the system as a whole and subsequent impact on the right ventricle (RV). The impact on the entire circulation is largely assessed invasively with flow and pressure sensors. These measurements can also be modeled based on invasive studies in humans and animals. Large arteries are most susceptible to alteration in elastin/collagen matrix and can be directly imaged with multiple modalities; reliable noninvasive physiological assessment has been technically challenging but is showing increasing feasibility with the latest technological advances. Small arteries are most susceptible to smooth muscle cell (SMC) hypertrophy and changes in tone, which can be assessed ex vivo with atomic force microscopy or examined histologically. The microcirculation suffers rarefaction and impaired angiogenesis with remodeling that can be best studied with micro-computed tomography (CT) or high-throughput, machine-assisted histology. CTA, computed tomography angiography; Dl_CO, diffusion capacity for carbon monoxide; mPAP, mean pulmonary artery pressure; MRA, magnetic resonance angiography; PFTs, pulmonary function tests; PP, pulse pressure; PVR, pulmonary vascular resistance; SV, stroke volume. Figure modified from Ref. , with permission from Frontiers in Physiology.

FIGURE 2.

Aging and mechanobiological signals intersect to regulate vascular remodeling and pulmonary vascular mechanics The schematic cross section of a pulmonary vessel highlights known aging-related changes in inflammation, senescence, and extracellular matrix remodeling in the vessel wall. On left are shown interacting aging mechanisms of senescence, inflammation, and mitochondrial and endothelial dysfunction that together influence pulmonary vascular biology. These mechanisms engage in reciprocal interactions with the mechanobiological cellular responses to altered shear stress, stiffness, pulsatile flow, and vascular distension shown on right. Within each of these domains are shown key pathways that are increased (green) or decreased (red) in response to aging and mechanobiological cues and that link these interacting mechanisms to each other and to vascular biology. Both sets of pathways are self-reinforcing positive feedback loops containing reciprocal interactions and lacking a single initiating pathogenic mechanism. Together the interaction of aging-related and mechanobiological cues drives structural and function alterations in the pulmonary vasculature, including extracellular matrix (ECM) remodeling, increased vascular tone, and microvascular dysfunction. Over time these changes combine to alter local and systemwide pulmonary vascular mechanics and function. eNOS, nitric oxide synthase 3 or endothelial NOS; MMPs, matrix metalloproteinases; MRTF, myocardin-related transcription factor; NF-κB, nuclear factor-κB; NRF2, nuclear factor-erythroid factor 2-related factor 2; ROS, reactive oxygen species; SMADs, small Mothers Against Decapentaplegic; TAZ, transcriptional coactivator with PDZ-binding motif; TGF-β, transforming growth factor beta; TNF-α, tumor necrosis factor alpha; YAP, yes-associated protein.