Role of Perivascular Adipose Tissue in Vascular Physiology and Pathology

HomeHypertensionVol. 69, No. 5Role of Perivascular Adipose Tissue in Vascular Physiology and Pathology Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBRole of Perivascular Adipose Tissue in Vascular Physiology and Pathology Zhen Fang Huang Cao, Elina Stoffel and Paul Cohen Zhen Fang Huang CaoZhen Fang Huang Cao From the Rockefeller University, Laboratory of Molecular Metabolism, New York, NY. , Elina StoffelElina Stoffel From the Rockefeller University, Laboratory of Molecular Metabolism, New York, NY. and Paul CohenPaul Cohen From the Rockefeller University, Laboratory of Molecular Metabolism, New York, NY. Originally published20 Mar 2017https://doi.org/10.1161/HYPERTENSIONAHA.116.08451Hypertension. 2017;69:770–777Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2017: Previous Version 1 Blood pressure (BP) regulation is a complex homeostatic process involving multiple organ systems, including the cardiovascular, renal, and central and peripheral nervous systems.1 Inability to properly regulate BP can result in the development of hypertension, which is associated with an increased risk of stroke, myocardial infarction, and cardiac and renal failure,2–4 and is the leading determinant of risk of death worldwide.5 In addition to genetic and environmental factors known to play a role in the development of hypertension,6 body weight and obesity are highly correlated with hypertension in humans.7,8 This is particularly alarming given the increased prevalence of obesity, which now affects 1 in 3 people in the United States.9 The close association between obesity, hypertension, and other cardiovascular disorders suggests an important role for adipose tissue (AT) in the regulation of vascular tone and BP.Until the mid 1900s, AT was considered to be a form of connective tissue with the primary function of storing energy in the form of lipids.10 However, AT is now recognized to be an important endocrine organ that can secrete polypeptides and metabolites, known as adipokines, which are involved in the normal regulation of various physiological processes, including BP regulation and vascular function.10,11 In the setting of obesity, AT undergoes complex remodeling. This is marked by a significant increase in tissue mass, through adipocyte hyperplasia and hypertrophy. Changes in structural and cellular composition also occur, including changes in AT extracellular matrix, composition of lipid droplets, and infiltration of immune cells such as macrophages and lymphocytes, which results in low-grade inflammation.10,11 Most importantly, obesity shifts the secretory profile of AT, which in turn contributes to the dysregulation of BP and eventual development of hypertension.12 This is thought to occur through both direct actions of circulating adipokines on the vasculature and indirect actions through other systems, including the renal, central, and peripheral nervous system. Leptin, which is elevated in obesity, increases BP through activation of central nervous system pathways and enhanced sympathetic nervous system output.13,14 In addition, AT affects the renal system through renal compression with increased AT mass, as well as through activation of the renin–angiotensin–aldosterone system, of which all components are also expressed in AT and increased in obesity.15 Increased expression of proinflammatory adipokines in obesity, such as tumor necrosis factor-α, promotes vascular dysfunction through alterations in endothelial cell function and thickening of the vascular smooth muscle layer. This, in turn, leads to increased oxidative stress and stiffening of the vascular wall, promoting changes in vessel reactivity.16,17The exact mechanisms by which AT regulates vascular function under normal conditions and obesity have been challenging to pinpoint due to location-dependent heterogeneity of AT phenotype. An increasing emphasis has been placed on understanding the role of AT surrounding the vasculature, known as perivascular AT (PVAT), given its location and potential role in paracrine and endocrine signaling. Here, we provide a brief review of the work assessing the role of PVAT in vascular regulation and the potential mechanisms by which PVAT may play a role in the development of hypertension and cardiovascular disease, with an emphasis on recently published work. We also highlight important unanswered questions in this emerging field.Perivascular FatLarge conduit vessels and small resistance vessels throughout the body are composed of a single layer of endothelial cells, vascular smooth muscle cells (VSMCs) making up the vessel wall, and an outer adventitial layer, composed of fibroblasts and extracellular matrix components. A layer of PVAT surrounds all blood vessels, except for the vasculature in the brain (Figure [A]).18–20 The phenotype of PVAT is highly dependent on the location of the vascular bed and vessel type and even species. For example, rat mesenteric PVAT is considered to be white AT (WAT) because it primarily contains white, energy storing, unilocular adipocytes.21 PVAT surrounding the femoral artery of mice and human radial artery is considered to be WAT.22,23 PVAT surrounding coronary arteries in humans has histological and gene expression characteristics resembling WAT but differs from WAT in adipocyte size and state of differentiation.24 On the other hand, rat and mouse aortic PVAT is considered to have a mixed phenotype, containing both energy dissipating thermogenically active, multilocular brown adipocytes and white adipocytes.25,26 This mixed phenotype, characterized by high levels of thermogenic gene expression such as UCP-1 (uncoupling protein-1), is more characteristic of classical brown AT (BAT), than WAT.27 However, even within a specific vascular bed, PVAT can have different phenotypes. For example, histological and functional studies show that mouse thoracic aortic PVAT exhibits greater similarity to BAT, whereas abdominal PVAT more closely resembles WAT.28 Generally, large conduit vessels are characterized by both brown- and white-like AT, whereas resistance vessels, which are critical in regulation of BP, tend to contain predominantly white-like AT.29,30Download figureDownload PowerPointFigure. Perivascular adipose tissue and regulation of vascular tone. A, Blood vessels are composed of a single, inner layer of endothelial cells, a layer of vascular smooth muscle cells (VSMCs) making up the vascular wall, an outer adventitial layer, and a layer of perivascular fat. B, Regulation of vascular tone by perivascular adipose tissue in lean conditions is known to depend on the secretion of adipokines. These adipokines act on endothelial cells, through a nitric oxide (NO)–dependent mechanism, as well as directly on smooth muscle cells to induce vasorelaxation of the vessel wall. C, In states of obesity, the secretory profile of perivascular adipose tissue is known to change, with a reduction of expression of vasorelaxing factors and an increase in secretion of vasoconstricting factors. In addition, expression of factors involved in immune cell infiltration and VSMC proliferation are also increased, leading to a general state of inflammation of perivascular tissue and thickening of the arterial wall.Although adipocytes in PVAT can be classified into traditional white and brown adipocytes, evidence suggests that PVAT adipocytes do not share the same developmental origin as adipocytes from classical BAT and WAT. Instead, it is believed that mature adipocytes within each AT depot are likely derived from distinct embryonic lineages.31 Human PVAT from coronary arteries shows differential expression of certain developmental and pattern forming genes compared with subcutaneous AT.32 In addition, deletion of PPAR-γ (peroxisome proliferator–activated receptor-γ), a master regulator of adipocyte differentiation,10 in VSMCs of mice resulted in a lack of PVAT development in these animals, whereas BAT and WAT remained intact, indicating that PVAT adipocytes may arise from VSMC progenitors.33As with the phenotype, the secretory profile of PVAT is also distinct from other AT depots, such as white visceral AT and subcutaneous AT depots, and differences also exist even between different PVAT depots. In comparison to visceral AT and subcutaneous AT within the same subject, human coronary PVAT produces less adipokines, including leptin, resistin, and adiponectin, and has decreased levels of markers of adipocyte differentiation.27,32 PVAT also produces higher levels of angiogenic factors and proinflammatory cytokines such as vascular endothelial growth factor, hepatocyte grow factor, IL-6 (interleukin-6), and MCP-1 (monocyte chemotactic protein-1).23,32 The gene expression profile of mouse aortic PVAT is far more similar to that of BAT than WAT. In addition, WAT-like mesenteric rat PVAT has been shown to express components of the renin–angiotensin–aldosterone system at substantially higher levels than BAT-like aortic PVAT.25 Given significant differences between vascular bed–dependent PVAT depots, it is possible that different PVAT depots may display distinct functions and mechanisms in the regulation of the vasculature. Therefore, caution must be exercised when interpreting results from studies and in generalizing the function of PVAT in vascular tone because different PVAT depots are often used in different studies.Although there is no direct evidence linking PVAT and the development of hypertension, correlative data suggest that PVAT likely plays a role. Just like total AT mass, PVAT mass is increased in obesity in both animal models and humans.34–37 In humans, PVAT mass is most closely correlated with visceral AT mass, a known predictor of the development of metabolic disease, including hypertension, in obese patients.34,36,38,39 Studies have also demonstrated that volume of PVAT alone is associated with hypertension and aortic and coronary calcification.36,40 On the other hand, in rat models of hypertension without obesity, such as spontaneously hypertensive rats, angiotensin II–infused rats, and deoxycorticosterone acetate salt rats, PVAT mass is consistently lower than in controls.25,41,42 This suggests that the functional integrity of PVAT, rather than the amount of PVAT itself, is essential in the control of BP and protection against the development of hypertension and cardiovascular disease.PVAT and Vascular ReactivityUntil recently, our understanding of the function of PVAT under normal physiological conditions was limited to its role in providing mechanical support for the vasculature. In fact, many studies investigating vessel function even removed the AT surrounding the vasculature because of potential interference with diffusion of exogenous substances or mechanical hindrance of vasocontractility. Soltis and Cassis43 were the first to challenge this notion. In their seminal 1991 study, they demonstrated that the presence of PVAT significantly reduced the contractile response of aortic preparations of lean rats to norepinephrine when compared with PVAT-free aortic preparations. Further studies demonstrated that the anticontractile effect of PVAT was not limited to norepinephrine because it was also observed with other vasoconstrictors, including angiotensin II, serotonin, endothelin-1, and phenylephrine.44 This phenomenon has been demonstrated in different vascular beds, including mesenteric, coronary, and limb vessels, as well as veins, indicating that the phenotype of PVAT is not a major determinant of this response.45–47 In addition, this effect has been observed across several mammalian species, including in human vessels.48Extensive studies on the anticontractile effects of PVAT have demonstrated that this property is not due to physical and mechanical interference since the transfer of a PVAT-incubated solution to PVAT-free vessel preparations is sufficient to produce vessel relaxation.44 The factor mediating this phenomenon is adipocyte derived, and its release is calcium dependent and regulated by a tyrosine kinase and protein kinase A.44,49 Mechanistically, the response is mediated by potassium (K) channels, in particular adenosine triphosphate (ATP)–dependent potassium channels (KATP) and voltage-gated K channels.45,49 In addition, the effect is both endothelium dependent, through nitric oxide (NO), and endothelium independent.34 Many PVAT-derived factors have been proposed to mediate this effect, now termed PVAT-derived relaxing factor, including adiponectin, angiotensin 1–7, free fatty acids such as methyl palmitate, and hydrogen sulfide gas, among others (Figure [B]).17 It is believed in the field that PVAT-derived relaxing factor is likely not a single molecule, and different factors may act as PVAT-derived relaxing factor depending on the vascular bed studied.Under normal conditions, the anticontractile effect is dependent on PVAT mass. However, in states of obesity, the effect is significantly decreased, despite an increase in PVAT mass.50 Although not fully understood, this functional change has been attributed to changes in PVAT secretory profile, oxidative stress in PVAT, and macrophage infiltration and inflammation in obesity (Figure [C]).16 PVAT expression of adiponectin and angiotensin 1–7, as well as other PVAT-derived relaxing factor candidates, is known to be reduced in obesity, whereas expression of the proinflammatory cytokine tumor necrosis factor-α is increased.17 In addition to the relaxing effects of PVAT, contractile effects have also been reported, particularly in the context of obesity.51–53 Studies show that PVAT plays a role in electrical stimulation-induced contraction of vessels and perivascular nerve stimulation, with some proposing that angiotensin II and norepinephrine in PVAT play a role, both of which are elevated during obesity.43 Others have proposed that cyclooxygenase and chemerin, also elevated with increased AT mass, play roles in the contractile effects of PVAT in obesity.52,54 As with the relaxing effects of PVAT, the contractile effects are probably not mediated by a single factor either. Overall, this contractile effect is thought to be highly dependent on the physiology of the organism, as well as the location of the vascular bed and PVAT.55An interesting recent study investigated the role of maternal obesity on the anticontractile effects of PVAT in offspring in rats.56 Many studies have shown that maternal obesity leads to increased AT accumulation and subsequent cardiometabolic disorders in offspring.57–59 The study demonstrated that the anticontractile effect of PVAT was lost in chow-fed offspring of diet-induced obese mothers at 12 and 24 weeks of age, compared with offspring of lean mothers, despite no differences in body weight between the groups. BP was also significantly higher in these animals at 15 and 24 weeks of age. This was primarily attributed to a reduction in PVAT-derived NO and an unidentified PVAT contractile factor. In addition, although maternal obesity can lead to endothelial dysfunction in offspring, endothelial function was normal at 12 weeks of age, when changes in PVAT function were observed. These results indicate that PVAT dysfunction precedes the development of obesity, endothelial dysfunction, and hypertension and demonstrates that normal PVAT function is subject to fetal programming and affected by maternal obesity.56Proinflammatory Phenotype of PVATPVAT-derived adipokines and cytokines have many other paracrine functions under normal physiological and pathological conditions, including regulating the endothelial release of vasodilators and vasoconstrictors, VSMC migration and proliferation leading to enlargement and stiffening of the arterial wall, and inflammatory cell migration leading to vascular dysfunction.16,17 The role of traditional adipokines and cytokines such as leptin, adiponectin, and tumor necrosis factor-α has been well studied. Novel factors and their functions are continuously being identified, in particular given the advances in genomic, proteomic, and biochemical analytic techniques in the last decade. The most extensively studied PVAT-derived adipokines and cytokines with roles in vascular regulation are summarized in Table. Of note, all of these factors are also made by other ATs. Thus far, no PVAT-selective adipokines or cytokines have been described.Table. Role of Known PVAT-Derived Factors in Vascular RegulationPVAT-Derived FactorΔ in ObesityRole in Vascular RegulationLeptinIncreaseInduces vasorelaxation via endothelial cells and VSMCs60Promotes VSMC proliferation61Induces vascular permeability62Stimulates SNS63AdiponectinDecreaseIncreases NO production and vasodilation64Protects from endothelial dysfunction65,66ResistinIncreaseIncreases VSMC proliferation/migration67Increases TNF-α and IL-6 production in WAT68Enhances endothelin-1 release69VisfatinIncreaseIncreases VSMC proliferation/migration26TNF-αIncreaseDecreases adiponectin expression/release70Induces IL-6, CRP production71Impairs NO-mediated vasodilation29,72Induces ROS production73Decreases eNOS signaling73Enhances VSMC proliferation74ChemerinIncreaseDecreases eNOS signaling and NO production75Stimulates inflammatory cell migration76Increases ROS stimulation77Increases myoblast proliferation77IL-6IncreaseRecruits inflammatory cells78MCP-1IncreaseRecruits inflammatory cells79Contributes to atherosclerosis and plaque vulnerability80PAI-1IncreaseIncreases VSMC proliferation81Prevents endothelial dysfunction82,83ROSIncreasePromotes contractile effects50H2SDecreaseDirectly anticontractile84NODecreaseParticipates in anticontractile effects18ANG IIIncreaseDirectly contractile85ANG 1–7DecreaseParticipates in anticontractile effects86ProstacyclinDecreaseDose-dependent anticontractile and contractile effects87Protects from endothelial dysfunction88Methyl palmitateDecreaseParticipates in anticontractile effects89Other fatty acidsIncreaseIncreases VSMC proliferation90Complement 3IncreaseInduces fibroblast migration42Induces macrophage secretion of TNF-α91ANG 1–7 indicates angiotensin 1–7; ANG II, angiotensin II; CRP, C-reactive protein; eNOS, endothelial nitric oxide synthase; H2S, hydrogen sulfide; IL-6, interleukin 6, MCP-1, monocyte chemoattractant protein-1; NO, nitric oxide; PAI-I, plasminogen activator inhibitor-1; PVAT, perivascular adipose tissue; ROS, reactive oxygen species; SNS, sympathetic nervous system; TNF-α, tumor necrosis factor-α; VSMC, vascular smooth muscle cell; and WAT, white adipose tissue.An interesting feature of PVAT is its adaptability to environmental stimuli such as a high-fat diet, more readily promoting a proinflammatory state than other AT depots.32 Mice fed a high-fat diet for only 2 weeks had reduced expression of anti-inflammatory and increased expression of proinflammatory adipokines and cytokines in PVAT of the aortic arch, whereas only minor changes were seen in visceral AT and subcutaneous AT in the same animals. These expression changes are a direct response of adipocytes in PVAT to metabolic stress as they occur before any observable infiltration of inflammatory cells into the tissue.32 This suggests a potentially important role for PVAT-derived proinflammatory factors in the development of vascular dysfunction and cardiovascular disease.Two particularly well-studied PVAT-derived proinflammatory cytokines are MCP-1 and IL-6, which play a significant role in the recruitment of inflammatory cells and the pathology of vascular disease in obesity. MCP-1 is one of the key chemokines that regulate migration and infiltration of monocytes and macrophages.79 Two weeks of high-fat diet feeding caused a ≈50-fold increase in MCP-1 expression in PVAT compared with other AT depots.32 Consistent with these findings, animal models with an MCP-1 gene deletion showed significantly reduced infiltration of inflammatory cells and lipid deposition into arterial walls, which would be expected to result in reduced arterial stiffness.79 MCP-1 is therefore likely to be a proinflammatory cytokine involved in vascular disease. Similar observations were made for IL-6, a proinflammatory cytokine with pleiotropic roles, including promoting arterial stiffening through cross-linking of extracellular matrix proteins such as collagen type I. IL-6 was also found to be secreted at higher concentrations from PVAT compared with other fat depots, and its expression is further elevated in obesity.32 Other studies investigating IL-6 in the context of arterial stiffness show increased levels of IL-6 in animals with elevated plasma cholesterol.92 On the basis of the observation that IL-6 inhibition reduces intrinsic mechanical stiffness in low-density lipoprotein receptor knockout mice, this cytokine may be a direct contributor to arterial stiffness and possibly cardiovascular disease risk.93Another PVAT-derived adipokine of interest is chemerin, which can cause contraction in arteries when applied without PVAT.54 Chemerin is produced in higher quantities in animals fed a high-fat diet and is linked to adipogenesis through the activation of ChemR23.94 ChemR23-deficient mice have reduced adiposity and body weight.95 Higher levels of chemerin correlate with chronic inflammation, marked by increased levels of tumor necrosis factor-α, IL-6, and C-reactive protein.96,97 In the vasculature, chemerin decreases NO-dependent cGMP signaling, thereby reducing vascular dilation in rat aortas by mechanisms involving reactive oxygen species and redox signaling.75 The underlying mechanism has been proposed to be because of generation of reactive oxygen species, which interferes with the MAPK pathway leading to proinflammatory responses in endothelial cells. Furthermore, chemerin induces proliferation and apoptosis of VSMCs through redox-sensitive processes. Its effects on endothelial dysfunction have been attributed to downregulation of endothelial nitric oxide synthase and a subsequent decrease in NO production.77 Chemerin is also able to amplify electric field–stimulated contraction in rat mesenteric artery preparations through the ChemR23 receptor.98 These findings suggest that chemerin may be an important mediator in the crosstalk between adipocytes and the vasculature, which under pathological conditions can act as a stimulus promoting apoptosis, inflammation, and smooth muscle proliferation. Therefore, chemerin might play an especially important role in the development of vascular injury in obesity-induced hypertension.PVAT and Regulation of the Autonomic Nervous SystemAT is highly innervated by the sympathetic nervous system, with nerve endings directly innervating adipocytes or arteries.99,100 In addition, a hallmark of obesity-induced hypertension is an increase in sympathetic nerve activity.101 Both vascular and metabolic responses of AT are regulated by the autonomic nervous system. Histological studies demonstrate the presence of catecholamines, in particular norepinephrine, in PVAT,102 which has created an increasing interest in the physiological function of this system in PVAT in the pathogenesis of essential hypertension.A recent study indicated that tyramine, a sympathomimetic, causes dose-dependent contraction in isolated thoracic aorta and superior mesentery artery preparations with intact PVAT, but not PVAT-free preparations.102 This effect was inhibited by an adrenergic α-1 receptor blocker, indicating that tyramine facilitates the release of catecholamines from PVAT. Norepinephrine was observed in the cytoplasm of adipocytes in PVAT, and sympathetic denervation did not reduce contraction to tyramine in mesenteric arteries with PVAT in which norepinephrine content was only modestly reduced. This suggests that PVAT contains a reservoir of functional catecholamines independent of the sympathetic nervous system. Another recent study indicates that PVAT has the ability to absorb norepinephrine through the norepinephrine transporter, serotonin transporter, and organic cation transporter 3 since norepinephrine uptake is reduced in the presence of inhibitors of these transporters.103 This uptake of norepinephrine could represent a mechanism by which PVAT modulates vascular tone under normal physiological conditions and could be dysregulated in disease. Considering that alterations in the adrenergic nervous system can have an effect on hypertension, approaches targeting the PVAT pathway may reveal novel therapeutic targets.Future DirectionsThe emerging data point to an important role for PVAT in normal physiology and in several pathological conditions. Many key unanswered questions remain. First, what is the developmental origin of perivascular adipocytes and might it differ based on the vascular bed? At this point, it is not clear whether perivascular fat cells share an origin with white, brown, or beige fat or perhaps come from another lineage altogether. Second, what is the full phenotypic spectrum of PVAT? Specifically, we do not yet know the full complement of vasoactive substances that can be produced by PVAT, and which of these might be location specific. Current developments in RNA sequencing technologies should facilitate more thorough gene expression comparison studies between multiple AT depots, as well as between different PVAT depots. Moreover, PVAT may play important roles in other aspects of biology, such as energy metabolism, that have yet to be described. Third, ongoing research is needed to dissect the link between PVAT, in particular the different phenotypes of PVAT, and disease. Do alterations in PVAT biology in the setting of obesity, for example, result in local and systemic effects that contribute to hypertension, atherosclerosis, aneurysm formation, and other vascular disease? Does BAT-like thoracic aortic PVAT play a different role than WAT-like abdominal or mesenteric PVAT in the regulation of vascular tone and disease development? At this point, most of the evidence linking the role of PVAT and vascular disease is correlative, with little direct evidence. This is primarily because of the fact that currently only a few ways exist to specifically manipulate PVAT versus other AT depots. Chang et al33 were able to ablate PVAT by crossing SM22α-Cre with PPAR-γ-floxed mice to study the role of thermogenic capacity of PVAT in atherosclerosis. However, more precise manipulations would be required to further dissect the function of PVAT and its various vascular bed–specific depots. A better understanding of the developmental origin of perivascular adipocytes and the phenotype and gene expression patterns of different vascular bed–dependent PVAT depots could provide depot-specific genetic markers, which would then allow for targeted manipulations of perivascular adipocytes. Basic and translational research into the biology of PVAT raises the exciting prospect that this tissue could one day be targeted therapeutically to alleviate the ever-growing burden of obesity-associated disease.DisclosuresNone.FootnotesCorrespondence to Paul Cohen, The Rockefeller University, Laboratory of Molecular Metabolism, New York, NY 10065. E-mail [email protected]References1. DeMarco VG, Aroor AR, Sowers JR. The pathophysiology of hypertension in patients with obesity.Nat Rev Endocrinol. 2014; 10:364–376. doi: 10.1038/nrendo.2014.44.CrossrefMedlineGoogle Scholar2. 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