RESUMO
Patients with chronic kidney disease (CKD) are at a highly increased risk of cardiovascular complications, with increased vascular inflammation, accelerated atherogenesis and enhanced thrombotic risk. Considering the central role of the endothelium in protecting from atherogenesis and thrombosis, as well as its cardioprotective role in regulating vasorelaxation, this study aimed to systematically integrate literature on CKD-associated endothelial dysfunction, including the underlying molecular mechanisms, into a comprehensive overview. Therefore, we conducted a systematic review of literature describing uremic serum or uremic toxin-induced vascular dysfunction with a special focus on the endothelium. This revealed 39 studies analyzing the effects of uremic serum or the uremic toxins indoxyl sulfate, cyanate, modified LDL, the advanced glycation end products N-carboxymethyl-lysine and N-carboxyethyl-lysine, p-cresol and p-cresyl sulfate, phosphate, uric acid and asymmetric dimethylarginine. Most studies described an increase in inflammation, oxidative stress, leukocyte migration and adhesion, cell death and a thrombotic phenotype upon uremic conditions or uremic toxin treatment of endothelial cells. Cellular signaling pathways that were frequently activated included the ROS, MAPK/NF-κB, the Aryl-Hydrocarbon-Receptor and RAGE pathways. Overall, this review provides detailed insights into pathophysiological and molecular mechanisms underlying endothelial dysfunction in CKD. Targeting these pathways may provide new therapeutic strategies reducing increased the cardiovascular risk in CKD.
Assuntos
Suscetibilidade a Doenças , Células Endoteliais/metabolismo , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Toxinas Urêmicas/efeitos adversos , Animais , Apoptose , Biomarcadores , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Estresse do Retículo Endoplasmático , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/metabolismo , Humanos , Óxido Nítrico/metabolismo , Estresse Oxidativo , Processamento de Proteína Pós-Traducional , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/terapia , Transdução de SinaisRESUMO
Ion channels in vascular smooth muscle regulate myogenic tone and vessel contractility. In particular, activation of calcium- and voltage-gated potassium channels of large conductance (BK channels) results in outward current that shifts the membrane potential toward more negative values, triggering a negative feed-back loop on depolarization-induced calcium influx and SM contraction. In this short review, we first present the molecular basis of vascular smooth muscle BK channels and the role of subunit composition and trafficking in the regulation of myogenic tone and vascular contractility. BK channel modulation by endogenous signaling molecules, and paracrine and endocrine mediators follows. Lastly, we describe the functional changes in smooth muscle BK channels that contribute to, or are triggered by, common physiological conditions and pathologies, including obesity, diabetes, and systemic hypertension.
Assuntos
Cálcio/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Músculo Liso Vascular/metabolismo , Animais , Humanos , Potenciais da Membrana/fisiologia , Transdução de Sinais/fisiologiaRESUMO
PURPOSE OF REVIEW: In addition to their effects on glycemic control, two specific classes of relatively new anti-diabetic drugs, namely the sodium glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have demonstrated reduced rates of major adverse cardiovascular events (MACE) in subjects with type 2 diabetes (T2D) at high risk for cardiovascular disease (CVD). This review summarizes recent experimental results that inform putative molecular mechanisms underlying these benefits. RECENT FINDINGS: SGLT2i and GLP-1RA exert cardiovascular effects by targeting in both common and distinctive ways (A) several mediators of macro- and microvascular pathophysiology: namely (A1) inflammation and atherogenesis, (A2) oxidative stress-induced endothelial dysfunction, (A3) vascular smooth muscle cell reactive oxygen species (ROS) production and proliferation, and (A4) thrombosis. These agents also exhibit (B) hemodynamic effects through modulation of (B1) natriuresis/diuresis and (B2) the renin-angiotensin-aldosterone system. This review highlights that while GLP-1RA exert direct effects on vascular (endothelial and smooth muscle) cells, the effects of SGLT2i appear to include the activation of signaling pathways that prevent adverse vascular remodeling. Both SGLT2i and GLP-1RA confer hemodynamic effects that counter adverse cardiac remodeling.
Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Cardiotônicos/farmacologia , Sistema Cardiovascular/patologia , Sistema Cardiovascular/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Humanos , Estresse Oxidativo/efeitos dos fármacosRESUMO
The epidermal growth factor receptor (EGFR) belongs to the ErbB-family of receptor tyrosine kinases that are of importance in oncology. During the last years, substantial evidence accumulated for a crucial role of EGFR concerning the action of the angiotensin II type 1 receptor (AT1R) in blood vessels, resulting form AT1R-induced EGFR transactivation. This transactivation occurs through the release of membrane-anchored EGFR-ligands, cytosolic tyrosine kinases, heterocomplex formation or enhanced ligand expression. AT1R-EGFR crosstalk amplifies the signaling response and enhances the biological effects of angiotensin II. Downstream signaling cascades include ERK1/2 and p38 MAPK, PLCγ and STAT. AT1R-induced EGFR activation contributes to vascular remodeling and hypertrophy via e.g. smooth muscle cell proliferation, migration and extracellular matrix production. EGFR transactivation results in increased vessel wall thickness and reduced vascular compliance. AT1R and EGFR signaling pathways are also implicated the induction of vascular inflammation. Again, EGFR transactivation exacerbates the effects, leading to endothelial dysfunction that contributes to vascular inflammation, dysfunction and remodeling. Dysregulation of the AT1R-EGFR axis has been implicated in the pathogenesis of various cardiovascular diseases and inhibition or prevention of EGFR signaling can attenuate part of the detrimental impact of enhanced renin-angiotensin-system (RAAS) activity, highlighting the importance of EGFR for the adverse consequences of AT1R activation. In summary, EGFR plays a critical role in vascular AT1R action, enhancing signaling, promoting remodeling, contributing to inflammation, and participating in the pathogenesis of cardiovascular diseases. Understanding the interplay between AT1R and EGFR will foster the development of effective therapeutic strategies of RAAS-induced disorders.
Assuntos
Doenças Cardiovasculares , Receptor Tipo 1 de Angiotensina , Humanos , Angiotensina II/metabolismo , Receptores ErbB/metabolismo , Inflamação , Receptor Tipo 1 de Angiotensina/metabolismo , TirosinaRESUMO
3D printing technology is used to produce channels within hydrogels followed by endothelial cells (ECs)-seeding to establish in vitro vascular models. However, as built-in bulk hydrogels, it is difficult to incorporate additional cells and molecules into the crosslinked matrix to study the pathophysiological responses of healthy endothelium. In this study, freestanding in vitro vascular models (VMs) are developed using the coaxial cell printing technique and a vascular tissue-specific bioink. It has various advantages in plotting tubular cell-laden vessels with designed patterns, providing pump-driven circulating perfusion, generating endothelium without ECs-seeding, and implementing further expansions to study vascular pathophysiology. Following the maturation of endothelium, the VMs exhibit representative vascular functions (i.e., selective permeability, antiplatelets/leukocytes adhesion, and vessel remodeling under shear stress). Moreover, with the expansions of the VMs, the directional angiogenesis and inflammatory responses are demonstrated by giving asymmetric distributions of proangiogenic factors and an airway inflammatory ambience, respectively. Therefore, the freestanding, perfusable, and functional VMs can be useful devices to engineer diverse in vitro platforms for a wide range of biomedical applications, from modeling blood vessel relevant diseases to building vascularized tissues/organs.