Hypoxia-Inducible Factor-1α: Comparison
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Please note this is a comparison between Version 2 by Vivi Li and Version 1 by Matilde Alique.

Aging is one of the hottest topics in biomedical research. Advances in research and medicine have helped to preserve human health, leading to an extension of life expectancy. However, the extension of life is an irreversible process accompanied by the development of aging-related conditions such as weakness, slower metabolism, and stiffness of vessels. It also debated that aging can be considered an actual disease with aging-derived comorbidities, including cancer or cardiovascular disease. Currently, cardiovascular disorders, including atherosclerosis, are considered premature aging and represent the first causes of death in developed countries, accounting for 31% of annual deaths globally. Emerging evidence has identified hypoxia-inducible factor-1α as a critical transcription factor with an essential role in aging-related pathology, in particular, regulating cellular senescence associated with cardiovascular aging.

  • hypoxia-inducible factor-1α (HIF1α)
  • vascular aging
  • senescent cells
  • endothelial cells
  • vascular smooth muscle cells
  • atherosclerosis
  • extracellular vesicles

1. Hypoxia-Inducible Factors

Hypoxia-inducible factors (HIFs) are the product of a heterodimeric transcriptional factor subdivided into three-member families of nuclear transcriptional factors (HIF1, HIF2, and HIF3), each one including α and β (nuclear translocator) subunits. HIF is a constitutive factor that is evolutionary conserved and plays a critical role in oxygen (O2) homeostasis from invertebrates up to humans.
Moreover, HIF is involved in the physiological mechanisms that lead to homeostasis, such as energy metabolism, cell growth, survival, invasion, migration, and angiogenesis [35][1]. O2 levels regulate both HIF-1α and HIF-1β (or aryl hydrocarbon receptor nuclear translocator; ARNT) and associate with DNA-binding transcription factor proteins. HIF-1α is a ubiquitous factor expressed in nucleated cells, while HIF-2α and HIF-3α are cell type-specific factors that are mainly expressed in vascular endothelial cells (ECs), renal cells, liver cells, and some cells from the myeloid lineage [36,37][2][3].
HIF-1α performs its critical function in the maintenance of vascular homeostasis [38][4] by orchestrating angiogenesis and vascular wall repair [29,39,40,41][5][6][7][8]. In addition to its role in the formation of blood vessels for O2 delivery, HIF also regulates erythropoietin (EPO) production in the kidneys that, in turn, controls red blood cell production. Further, more than one hundred genes have been identified to be governed by mammalian HIF during O2 deprivation [42,43][9][10]. The involvement of HIF-1α in diseases of the vascular wall, including atherosclerosis, carotid stenosis, and aneurysms, has recently been proposed [44,45,46,47,48,49][11][12][13][14][15][16]. Indeed, insufficient expression of HIF is associated with CVD [50,51][17][18]. Moreover, short-term HIF overexpression has beneficial effects on the heart, and long-term HIF stabilization is associated with cardiomyopathy [52][19]. Recent emerging data reveal crosstalk between HIF-1α and cellular senescence-associated cardiovascular aging (Table 1) [3,29,52,53,54][20][5][19][21][22].
Table 1. The role of hypoxia-inducible factors in cardiovascular aging.
HIF Levels Observations Reference
Pathology/Effect Tissue/Cell Type
↑ Ischemic cardiovascular disease Ischemic limb

(ischemic calf muscle)

(young WT mice)		 [54][22]
↓ Ischemic limb

ischemic calf muscle

(aging WT mice)
↓ Vascular remodeling Femoral artery ligation in aging mice [53][21]
↓ Femoral artery ligation in Hif1a+/− mice
↑ (short-term) Heart homeostasis Heart [52][19]
↑ (long-term) Cardiomyopathy
↓ Atherosclerosis

(Premature aging disease)		 Pathogenesis of plaques

(Promote angiogenesis, production of factor pro-atherosclerosis and recruitment of inflammatory cells)		 [3][20]
↓ Replicative senescence in vitro Endothelial cells [29][5]

2. The Physio-Pathological Role of HIF in Aging

Since the discovery of HIF-1α, several seminal works have identified the changes in HIF associated with age and the development of age-related disorders [55][23], including neurodegenerative diseases [56][24]. Importantly, in 2009, Mehta et al. described HIF-1 as a longevity factor, demonstrating that HIF-1 stabilization is associated with a 30–50% increase in lifespan [57][25]. Several studies have shown that stabilization of HIF-1 increases longevity and healthspan through different pathways in Caenorhabditis elegans [58,59][26][27]. These critical findings in worms yielded a new perspective on the study of HIF stabilization and lifespan among mammals [60][28]. However, the stabilization of mammalian HIF-1α has been implicated in tumor growth and cancer development and may therefore be harmful. Consequently, a balance between the beneficial and detrimental effects of HIF is critical for homeostasis and depends on the involved components and their contribution to longevity. Members of the p53 family counteract HIF stability; as a consequence, the O2-independent regulation of HIF-1 impacts the tumorigenic potential of cancer cells, thereby affecting angiogenesis, metabolism, and metastasis [61][29].
Studies on skin, a tissue that is continuously exposed to intrinsic and extrinsic aging factors, have identified HIF-1α as a crucial determinant of skin homeostasis, especially in epidermal aging and wound healing [62][30]. Results have reported that the loss of epidermal HIF-1α accelerates epidermal aging and affects re-epithelialization in humans and mice [62][30]. Notably, significant elevations in both hypoxia-inducible transcription factors HIF-1α and HIF-1β gene expression have also been found in the gingival tissues of aged animals, even though these tissues were deemed clinically healthy [63][31]. In a model of limb ischemia in mice, HIF-1 was found to mediate angiogenesis and, therefore, has been proposed to contribute to the pathological aging process [54][22].
Aging per se is a consequence of other diseases called age-related pathologies, because the risk of organ failure and age-associated disease increases with the advance of age [1][32]. Atherosclerosis is primarily featured by senescent cells in advanced human atherosclerotic plaques, and aging is considered to be a dominant risk factor for disease development [64][33]. Indeed, some studies have shown that markers of senescent cells are found in atherosclerotic plaques but not in non-atherogenic arteries [5,65][34][35]. Moreover, the arteries from older healthy adults and hypertensive patients have higher expression of p21, a marker of senescence, as well as the SASP pro-inflammatory phenotype [66][36]. In the vascular wall, the SASP phenotype is responsible for the enrichment of the pro-inflammatory milieu. Both interleukin (IL)-6 and IL-8, through a paracrine effect, cause negative feedback over cellular growth and contribute to maintenance of the senescent phenotype [67][37]. Notably, in this case, the molecular program of senescence is HIF-dependent [68][38]. Likewise, ECs sampled from healthy older adults have higher expression of the senescence markers p21 and p16, both of which are correlated with blunted endothelial function [69][39].
By contrast, older adults that perform regular exercise, which may be considered a vasoprotective lifestyle factor, have normalized endothelial senescent markers and endothelial function [5][34]. Moreover, some mediators, such as miRNAs, are described to have a critical role in (patho)physiological processes, including atherosclerosis [70,71,72][40][41][42]. In particular, miR-126 exerts an atheroprotective effect [72,73][42][43] due to its role in restoring endothelium homeostasis [74][44].
Concretely, miR-126 modulates stromal cell-derived factor-1 (SDF-1) and vascular cell adhesion molecule-1 (VCAM-1) in ECs [75][45]. During endothelial dysfunction, miR-126 levels are decreased and as a consequence, an augmented SDF-1 expression improves stroke outcome [75,76][45][46]. However, miR-126 modulates C-X-C chemokine receptor type 4 (CXCR4) protein levels during atherosclerosis. As a result, SDF-1 is released and increase the recruitment of endothelial progenitor cells to the atheroma plaque [77][47]. Nowadays, miR-126 has been described as a dual regulator of atherosclerosis [77][47]. On the one hand, miR-126 induced SDF-1, which promoted endothelial progenitor cells during atheroma formation. As a consequence, VCAM-1 expression is inhibited and EC proliferation limited atherosclerosis progression. In this way, atherosclerosis formation is impeded and miR-126 shows a beneficial role in atherosclerosis [76,77][46][47]. On the other hand, few studies showed that miR-126 presents adverse effects in atherosclerosis. Mir-126 affects the proliferation and apoptosis of VSMCs and also these cells do not express miR-126 during atherosclerosis [78][48]. In contrast, Hao and Fan showed that miR-126 is upregulated in atherosclerosis lesions in mice [79][49]. In conclusion, the presence of miR-126 in ECs has beneficial effects in atherosclerosis, whereas miR-126 in VSMCs exacerbated atherosclerosis.
Despite the complex relationship between HIF and aging, Kaluz et al. recently noted that several age-associated maladies involve the disarray or activation of the hypoxia response mechanism, mainly the HIF transcriptional factor [3][20]. In part, this phenomenon could be related to evidence for the overactivation of hypoxia responses to a modestly slow aging life, associated with beneficial stress responses in various animal studies. These findings support the idea of targeting HIF in early age-related diseases to slow down aging and prevent the progression of aging-related diseases. The authors concluded that an “HIF pill” could be preventive in the development of early age-related disease, thereby slowing the progression of aging. Recently, Semenza [80][50] summarized the HIF stabilizers registered in clinical trials for anemia, a common complication of CKD. We propose that HIF stabilization with the treatment of these drugs could help prevent age-related disease.
We summarize the role of HIF under physiological and pathological conditions (age-associated diseases included) in Figure 1.
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Figure 1. Schematic illustration of HIF’s role in homeostasis (physiological conditions) compared with the pathological situation (age-associated diseases included).

3. HIF-1α and Vascular Aging

As mentioned above, HIF is not only a transcriptional factor that regulates tissue oxygenation (including angiogenesis and vascular remodeling) but also controls redox balance, inflammation, and glucose metabolism to eventually maintain cellular homeostasis [36,61][2][29].
According to current knowledge, the age-dependent impairment of HIF-1α induction leads to diminished vascular responses to limb ischemia [54][22] and less effective wound healing [81][51]. Some evidence shows the functionally important expression of HIF-1α among ischemic limb mice. It has been demonstrated that the abundance of the HIF-1α protein is decreased in ischemic tissues from aged mice and has also been linked with the downregulation of genes encoding angiogenic growth factors [61][29]. In this regard, Bosch-Mache et al. showed that reduced blood flow recovery among aged mice resembles the response of heterozygous HIF-1α knockout mice to ischemia [54][22]. Interestingly, the exogenous administration of constitutively active forms of HIF-1 into the ischemic limb was sufficient for overcoming the age-dependent impairment of ischemia-induced vascular remodeling in aged mice [54][22]. Thus, the ability of HIF signaling to regulate the angiogenic process may be one of the main factors in vascular aging. In this scenario, the HIF pill theory would provide a preventive treatment for vascular aging.
Some aging-related vascular diseases present a rapid course of regular age-dependent arterial changes called early vascular aging (EVA) [82][52]. Aging of the arterial wall vessels in humans can be quantified by measuring the pulse wave velocity along the aorta—the largest elastic artery—which represents a marker of arterial stiffness [82][52]. Superior techniques to evaluate EVA are the use of noninvasive procedures to determine arterial stiffness indexes, including the carotid intima–media thickness (IMT), central blood pressure, and endothelial damage parameters [82][52]. In this regard, EVA is also characterized by media vascular calcification (VC) in CKD. During chronic inflammation mediated by uremic toxins, VSMCs are significantly affected, becoming dysfunctional and causing VC, which may potentially be used as a biomarker for vascular age [16,83,84][53][54][55].
Aging is associated with transforming growth factor type β (TGF-β) inhibition via HIF-1 [85][56]. In addition to TGF-β signaling, there is crosstalk between the HIF pathway and well-known stress-related sensors, including AMPK (AMP-activated protein kinase), sirtuins, and nuclear factor-κB (NF-κB) [86][57]. Despite the role of sirtuins in the regulation of aging and longevity, nowadays, its role is still controversial [87][58]. Satoh et al. [87][58] described that sirtuin-1 activity is critical in the systemic regulation of tissue communication, aging, and longevity in mammals. Notably, overexpression of sirtuin-1 due to the calorie restriction diet plays a role in the pathogenesis of age-associated mitochondrial damage in aging kidney mice [88][59]. Recently, it has been demonstrated that sirtuin-1 and HIF-1α are connected [89][60]. In this sense, sirtuin-1 induced deacetylation of HIF-1α in aged kidneys, protecting tubulointerstitial damage [89][60]. Since 2012, it is well known that sirtuin-1 is necessary for HIF-1α protein accumulation [90][61] and the current knowledge is that sirtuin-1 could activate several transcriptional factors, such as HIF-1α, resulting in ameliorated mitochondria biogenesis and an extended lifespan [91][62]. In the pathophysiology of vascular aging and atherosclerosis, sirtuin-1 plays a protective role [92][63]. In endothelial dysfunction, the expression of sirtuin-1 is reduced promoting the manifestation of senescence in endothelial cells [93,94,95][64][65][66]. Moreover, sirtuin-1 modulates eNOS and NO production in vascular walls [92][63], playing a crucial role in maintaining vascular function and homeostasis.
Another vital player of vascular aging, which is positively regulated by HIF-1, is vascular endothelial growth factor (VEGF), a central mediator of angiogenesis. During aging, there is a defect in HIF-1 activity, yielding VEGF expression reduction and leading to the impairment of angiogenesis in response to the ischemia model [96][67]. Similarly, EPO is directly regulated by HIF, and lower secretions of EPO have been observed among old animals [97][68] and elderly patients [98][69]. Furthermore, the transcriptional program controlled by HIF-1 includes genes involved in many aspects of cellular homeostasis, and HIF-1 abolishment by aging could generate defects in the physiological responses to hypoxia [96][67]. Recently, we found that HIF-1α is involved in p53, p16, cyclin D1, and lamin B1-mediated senescence in ECs [29][5]. Moreover, senescent ECs failed to express HIF-1α, and the microvesicles (MVs, an EVs subtype) released by these cells were unable to carry HIF-1α [29][5]. In another study, HIF-1α was found to play a critical regulatory role in vascular inflammation among macrophages after intimal injury through limiting excessive vascular remodeling. The mechanism by which macrophage-derived HIF-1α mediated this effect is still unknown [99][70]. Considering these findings, HIF-1α may represent a possible therapeutic target in vascular diseases, especially in vascular aging.

4. HIF and Atherosclerosis

Although atherosclerosis has been considered chronic inflammation, intensive research in recent years has shown that it can also be considered an age-related pathology [28,100][71][72]. Many pieces of evidence have demonstrated the role of vascular senescence in atherogenesis [25,101][73][74]. We briefly mentioned above that senolytic drugs (anti-senescence) have been proposed as a therapeutic option for cellular aging and for treating human atherosclerosis [25,28][73][71]. However, although gerontologists have affirmed that atherosclerosis is associated with the characteristic features of aging in humans, cardiologists believe that aging is not a risk factor for atherosclerosis. This controversial subject was re-evaluated by Minamino et al., who demonstrated that senescent vascular cells accumulate in human atheroma and that vascular cells present features of dysfunction [102,103][75][76]. These and other findings suggest that cellular senescence contributes to atherosclerosis, which is a characteristic of aging in humans. As a model for premature aging disorder, atherosclerosis is the most common type of vascular aging where the cell vessels are susceptible to damage. Adding to the complex scenario for atherosclerosis, many studies suggest that ECs and VSMCs change and acquire features of senescent cells [104][77]. Moreover, during aging, blood vessels experience changes in compliance and release pro-inflammatory factors that promote atherosclerosis. Aging is associated with chronic low-grade inflammation that affects vascular and endothelial cells within the vascular wall during atherosclerosis. It is reasonable to believe that low-grade systemic inflammation may facilitate the senescent phenotype of ECs, which also contributes to the local inflammatory environment by SASP. These aging endothelium walls impair angiogenesis and decrease coagulation activity [104][77]. In an aged endothelium, senescent ECs failed to achieve HIF-1α stabilization and decreased miR-126 levels, which are both essential contributors to the maintenance of endothelium homeostasis [29][5]. In the vasculature, HIF-1α regulates pressure changes due to the negative regulation of TGF-β in ECs [85][56] (note that pressure overload leads to increased myocardial O2 consumption). In this regard, the anoxemia theory is defined as a condition of abnormal oxygenation of the arterial blood. This theory proposes that an imbalance between the demand for and supply of O2 in the arterial wall is a critical factor in the development of atherosclerosis [105][78]. As a consequence, macrophages become apoptotic, a necrotic core is built, and there is an eventual increase in angiogenesis, linking senescent cells to atherosclerosis progression [7][79]. Therefore, the anoxemia theory is postulated to explain the progress of atheroma plaque. In 2007, the presence of HIF-1α was described in atheroma plaque [106][80]. HIF-1α is a regulator of angiogenesis and inflammation in atherosclerotic plaque destabilization. Moreover, HIF-1α is associated with an increase in VEGF levels during the inflammatory process in atheroma plaque. Notably, activated macrophages in atherosclerosis have been observed to stabilize HIF-1α under normoxic conditions [106][80]. HIF-1α stabilization occurs due to the local relative hypoxia resulting from insufficient O2 diffusion in the thickened intima and increased O2 demand due to the local inflammatory response. If the O2 supply is restored, HIF-1α is degraded, which reduces VEGF production and subsequent angiogenic signaling [107][81]. Another study reported that HIF-1α increases as a consequence of neovascularization in complicated human atherosclerosis among human carotids, as well as in coronary plaques [105][78]. Mechanistically, the angiogenic effect of the alternatively spliced tissue factor (asTF) activates HIF-1/VEGF signaling [41][8]. Indeed, activated macrophages localized in atheroma plaques expressed HIF1-α and VEGF, confirming that both are critical to the regulation of human plaque angiogenesis and lesion progression. Therefore, HIF-1α mediates inflammation by promoting pro-inflammatory cytokine expression and, consequently, inflammatory cell recruitment [108,109][82][83]. In macrophages, HIF-1α regulates the expression of one of the major pro-inflammatory cytokines, IL-1β [110][84]. Pro-inflammatory and pro-angiogenic activities are induced in endothelial cells exposed to IL-1β stimulation [111][85]. Notably, anti-inflammatory IL-1β therapy led to a significantly lower rate of recurrent cardiovascular events [112][86]. Another IL-1 family member, IL-1α, is mainly associated with endothelial cell senescence and atherosclerosis [113][87]. Both IL-1α and IL-1β are minor components of SASP; however, these two cytokines are essential for boosting IL-6 and IL-8, which are secreted in large quantities by senescent endothelial cells [114,115][88][89] (Figure 2).
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Figure 2. Molecular pathways linking HIF-1 to senescence during atherosclerosis.
Moreover, extensive crosstalk between HIF and two master regulators of the inflammatory response, NF-κB and the signal transducer and activator of transcription 3 (STAT3), has been reported [108,116,117][82][90][91]. Under hypoxic conditions, canonical NF-κB signaling activates HIF-1α through the interactions between p50 and p65 subunits and responsive elements in the promoter of the HIF-1α gene [118][92]. The crosstalk between HIF-1α and NF-κB signaling during senescence has been investigated in several contexts, and its role in orchestrating SASP is widely accepted in atherosclerotic plaques. However, the full mechanism of this crosstalk is not yet completely understood. Strikingly, Minamino et al. [104][77] demonstrated the presence of senescent vascular cells in human atherosclerotic lesions but not in non-atherosclerotic lesions. This study characterized some of the features of senescent cells and described an increase in pro-inflammatory mediators, including NF-κB signaling-dependent mediators, but a decrease in eNOS. In addition to these findings, signs of cellular senescence have also been detected in premature aging mouse models [119][93]. Together, these results provide in vivo evidence that links cellular senescence to organismal aging [104][77]. For instance, arterial remodeling during atherosclerosis progression is accelerated during aging. The accumulation of lipids in the arterial wall, followed by foam cell formation, is a response to endothelial damage and inflammation. Once the atheroma plaque is stable, it becomes an advanced plaque with increased susceptibility to rupture, leading to thrombosis [120][94]. Moreover, unstable plaque highlights the relationship between atherosclerosis and HIF-1α in ECs [121][95] and macrophages [122][96], independent of their origin (SASP or SIPS). It was also shown that the final step in atheroma plaque development is VC formation [7,123,124][79][97][98]. Aging causes calcification in vascular smooth muscle cells, which occurs independent of inflammation but causes arterial stiffening [120][94]. In this way, atherosclerosis, as well as aging or age-related atherosclerosis, causes vascular wall senescence and, as a consequence, VC—the final step of the pathology process. Increased VC in atherosclerosis produces numerous marked vascular effects, such as a reduction of tissue perfusion, which eventually causes end-organ damage, particularly in the elderly population [125][99]. EVs are essential modulators of vascular cell functions relevant to vascular inflammation and atherosclerosis [126,127][100][101]. Furthermore, EVs have been identified as cell-to-cell communicators. EV content includes proteins, lipids, and nucleic acids that are transferred to target cells [15,128][102][103] and modulate cell functions and phenotypes [129][104]. The abundance of EVs and the release of their cargos are augmented under inflammatory [129][104] and pathological conditions, including CVD, metabolic disorders, atherosclerosis, and DMII [129,130][104][105]. Platelets liberate EVs from vascular vessels (ECs and smooth muscle cells), erythrocytes, and leukocytes [131,132][106][107]. EVs may be potential biomarkers and pharmacological targets for atherosclerotic diseases and, therefore, may also be biomarkers for age-associated diseases, especially for EV-based therapeutics.

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