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Review
. 2022 Mar 18;130(6):928-941.
doi: 10.1161/CIRCRESAHA.121.319815. Epub 2022 Mar 17.

Endothelial Senescence: A New Age in Pulmonary Hypertension

Miranda K Culley  1 , Stephen Y Chan  1
Affiliations
Review

Endothelial Senescence: A New Age in Pulmonary Hypertension

Miranda K Culley et al. Circ Res. .

Abstract

Pulmonary hypertension is an enigmatic, deleterious disease driven by multiple heterogeneous causes with a burgeoning proportion of older patients with complex, chronic comorbidities without adequate treatment options. The underlying endothelial pathophenotypes that direct vasoconstriction and panvascular remodeling remain both controversial and incompletely defined. This review discusses emerging concepts centered on endothelial senescence in pulmonary vascular disease. This principle proposes a more heterogeneous, dynamic pulmonary endothelium in disease; it provides a potentially unifying feature of endothelial dysfunction in pulmonary hypertension irrespective of cause; and it supports a clinically relevant link between aging and pulmonary hypertension like other chronic illnesses. Thus, taking cues from studies on aging and age-related diseases, we present possible opportunities and barriers to diagnostic and therapeutic targeting of senescence in pulmonary hypertension.

Keywords: aging; arterial pressure; heart failure; pulmonary hypertension; vasoconstriction.

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Figures

Figure 1.
Figure 1.. Converging pathways of cellular senescence
In addition to appropriate physiologic processes like embryogenesis and wound healing, chronic stress-induced cellular senescence is dependent upon several triggers (highlighted in white), including mitochondrial oxidative damage, proteotoxic and endoplasmic reticulum (ER) stress, oncogene activation, epigenetic, DNA damage, and telomere instability. In response, senescent cells exhibit the following phenotypic characteristics: apoptosis resistance, production of the senescence-associated secretory phenotype (SASP), and permanent exit from the cell cycle. To start, upregulation of the B cell lymphoma family proteins (BCL-2, BCL-XL, BCL-W) prevents mitochondrial outer membrane pore formation, release of cytochrome c, and ultimately intrinsic programmed cell death. At the same time, multiple pathways like mTOR, p38 MAPK, and p53 activate transcription of cytokines, chemokines, proteases, and growth factors in the SASP profile. Lastly, in response to cumulative to genotoxicity, DNA damage response (DDR)-dependent signaling via p53-p21Cip and p16INK4a antagonizes cyclin-dependent kinases (CDK2, CDK4, CDK6) and in turn stabilizes the retinoblastoma protein (Rb) that suppresses cell cycle S-phase entry. Altogether, these characteristics prevent regeneration and promote inflammation-driven damage. Abbreviations: ROS – reactive oxygen species, JAK – Janus tyrosine kinase, mTOR – mammalian target of rapamycin, MAPK – mitogen-activated protein kinase, C/EBPB – CCAAT/enhancer-binding protein beta, NFκB – nuclear factor kappa-light-chain-enhancer of activated B cells, BRD4 – bromodomain-containing protein 4, ATM/R – ataxia-telangiectasia and Rad3 related serine/threonine kinases, ARF – alternate reading frame protein from CDKN2A locus
Figure 2.
Figure 2.. Working model of endothelial senescence-induced PH
Based upon the cumulative work of van der Feen et al. and Culley et al. with findings highlighted in white boxes, multiple triggers including hemodynamic stress, inflammation, and hypoxia across WSPH Groups 1, 2, and 3 induce senescence in a subpopulation of the pulmonary endothelium (depicted in dark blue). Mechanistically, deficiency of frataxin (FXN) in response to these stressors promotes replication stress and abrogates iron-sulfur (Fe-S)-dependent DNA polymerase δ (POLδ) and thus genomic stability, converging on DNA damage response-dependent senescence. The complete mechanism is not yet fully defined. In turn, up-regulation of the inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα) mediate vascular changes: neointimal formation, smooth muscle cell hypertrophy and proliferation, collagen deposition and vascular stiffening, and perivascular inflammation. With topics designated in gray boxes, further study is required to better understand 1) how additional triggers and known molecular mechanisms converge on senescence, 2) the interaction of senescent cells within a heterogeneous pulmonary endothelium, and 3) the complete profile and corresponding paracrine and endocrine effects of the senescence-associated phenotype (SASP).
Figure 3.
Figure 3.. Senotherapies target prosurvival and proinflammatory pathways
Evolving senotherapies can be broadly categorized into either senolytics or senomorphics. Those that have been tested in preclinical and clinical models of pulmonary hypertension (PH) are designated in red and those not yet tested in black. Specifically, therapies that induce apoptosis (senolysis) in senescent cells target multiple pro-survival pathways. The alkaloid phytochemical piperlongumine promotes mitochondrial oxidative damage; forkhead box O4 (FOXO4)-interacting peptide (DIR-FOXO4) antagonizes FOXO4 binding and allows for p53-driven apoptosis; B cell lymphoma 2 (BCL2) protein inhibitors (e.g., ABT-263, ABT-737, and in part quercetin) induce the intrinsic apoptosis pathway; and heat shock protein 90 (HSP90) chaperone inhibitors prevent stabilization of oncogenic and anti-apoptotic factors. Of note, treatment with the nonspecific tyrosine kinase inhibitor dasatinib (crossed out), used for senolysis in combination with quercetin, has resulted in PH development rather than prevention. Separately, therapies that inhibit the NFκB-dependent transcription directly (e.g., metformin, elafin) or indirectly via inhibition of mTOR and p38MAPK signaling or bromodomain-containing protein 4 (BRD4)-dependent transcription abrogate senescence-associated secretory phenotype (SASP) production. Alternatively, monoclonal antibodies can neutralize specific proinflammatory senescent secretome components. Abbreviations: ROS – reactive oxygen species, PI3K – phosphoinositide 3 kinase, AKT – protein kinase B, mTOR – mammalian target of rapamycin, MAPK – mitogen-activated protein kinase, NFκB – nuclear factor kappa-light-chain-enhancer of activated B cells, TNFα – tumor necrosis factor alpha, IL-6 – interleukin-6, IL-1/R – interleukin-1/receptor
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