Cardiovascular aging is accompanied by profound remodeling of the extracellular matrix (ECM). Growing evidence suggests that ECM not only acts as a structural scaffold but also actively regulates cell behavior and vascular homeostasis. During aging, the vascular ECM undergoes numerous molecular, architectural, and biochemical changes, including collagen accumulation, elastin fragmentation, pathological crosslinking, matrikines production, and progressive matrix stiffening. These changes reshape the vessel wall’s biochemical and mechanical landscape, reflecting how cells respond to their microenvironment. Vascular cells continuously interpret matrix-derived cues through integrins, discoidin, syndecans, ion channels, and downstream pathways such as FAK, RhoA/ROCK, and YAP/TAZ. As the ECM ages, continuous activation of these pathways promotes endothelial dysfunction, modulation of the vascular smooth muscle cell phenotype, fibroblast activation, inflammation, calcification, and induction of senescence. Consequently, the aging ECM emerges as an instructive niche that can determine and reprogram vascular cell identity and function. Interestingly, the relationship between ECM remodeling and senescent state is bidirectional. Senescent vascular cells profoundly affect matrix composition by producing a plethora of factors involved in ECM production and remodeling, while age-associated ECM alterations, including collagen deposition, increased stiffness, and active matrikines, can induce or reinforce senescence-associated phenotypes. This bidirectional interaction establishes a self-amplifying loop that accelerates vascular dysfunction and cardiovascular aging. In this work, we discuss the molecular and structural hallmarks of ECM aging, the mechanisms by which vascular cells sense and interpret matrix-derived signals, and emerging evidence linking ECM remodeling to senescence and vascular remodeling. In addition, we highlight unanswered questions and opportunities aimed at preserving ECM integrity, modulating mechanotransduction, and restoring a more youthful extracellular environment. In sum, this review supports the notion that aging ECM is not a passive bystander, but a pivotal driver and a promising intervention target for promoting vascular aging and cardiovascular diseases.
Abstract Sphingosine 1-phosphate receptor 1 (S1PR1) regulates vascular homeostasis and immune function, but its role in atherosclerosis has remained controversial because activating the same receptor produces divergent effects across cell types. This review synthesizes evidence on S1PR1 signaling in endothelial cells, macrophages, and vascular smooth muscle cells, and proposes a context-dependent framework, shaped by cell type, ligand presentation, and inflammatory environment, to reconcile these conflicting findings. In endothelial cells, S1PR1 preserves barrier integrity and limits leukocyte recruitment when activated by ApoM-bound HDL-S1P. In macrophages, it promotes anti-inflammatory polarization, cholesterol efflux, and efferocytosis via PI3K/Akt and LXR signaling. In vascular smooth muscle cells, by contrast, injury-induced S1PR1 drives proliferation and neointimal hyperplasia through IL-6/STAT3 signaling. This framework also explains the variable efficacy of S1PR1-targeting drugs, favoring selective, non-degrading agonists over functional antagonists, though murine-to-human differences in circulating S1P biology remain a key translational barrier. Future therapeutic strategies should prioritize cell-selective delivery, biased or non-degrading agonists, restoration of ApoM-mediated signaling, and biomarker-guided patient selection to maximize vascular protection while avoiding adverse remodeling.
Abstract Arterial stiffness predicts cardiovascular risk, particularly among individuals with hypertension. Recent studies suggest that gut microbiome influences arterial dysfunction. However, there is still a lack of randomized controlled trials (RCTs) evaluating the impact of probiotics on central hemodynamic parameters. The aim of the present study was to evaluate the effects of multi-strain probiotics supplementation on arterial stiffness and central blood pressure in adults with hypertension and excess weight on an energy-restricted diet. A secondary aim was to evaluate the association between changes in body adiposity and central hemodynamic parameters. This double-blind, randomized, placebo-controlled trial included adults (40–65 years) with hypertension and body mass index 25–39.9 kg/m 2 . Participants were assigned to two groups: one group received capsules containing eight probiotic strains (3 × 10 1 ⁰ CFU/day), while the other received placebo capsules. Both groups adhered to caloric restriction. Assessments for both groups were conducted at baseline (W0), week 6 (W6), and week 12 (W12). Initial evaluations included dietary intake, anthropometric measurements, body composition, blood pressure (BP), central hemodynamic parameters (including pulse wave velocity, PWV) and laboratory data. During the baseline visit, all participants were provided with an energy-restricted diet and capsules to be taken over the first six weeks of the study. At W6, anthropometric and BP measurements were repeated, and a new supply of capsules was issued. Comprehensive baseline assessments were performed again at W12. Sixty-six subjects were included in the RCT, 30 completed the study and performed the evaluation of central hemodynamic parameters, being included in the statistical analysis: 13 in the probiotics group and 17 in control group. The intergroup analyses showed no significant effect of probiotics on central hemodynamic parameters. There were positive and significative associations of changes (1) in body weight with modifications in aortic systolic BP, in augmentation pressure and in PWV, and (2) in visceral adipose tissue with modifications in PWV. In conclusion, multi-strain probiotics supplementation, over a 12-week period, did not improve arterial stiffness and other central hemodynamics parameters in individuals presenting hypertension and overweight/obesity following an energy-restricted diet. However, decreases in body adiposity were directly associated with improvement in PWV. The clinical trial was registered at www.ensaiosclinicos.gov.br : RBR-7jw4ry on 01/14/2020.
Abstract Background and Objective Obstructive sleep apnea (OSA) has been considered a risk factor for cardiovascular diseases. This study evaluated whether moderate or severe OSA attenuates the vascular benefits of weight loss induced by a short-term nutritional intervention in individuals with obesity. Methods Prospective 8-week energy restriction (-800Kcal/day) study included individuals aged 40–70 years with body mass index 30–40 kg/m 2 . Microvascular reactivity, heart rate variability, and central hemodynamics by oscillometry were evaluated at baseline and after 8 weeks. The sleep study was performed through a portable home device (WatchPAT-200). Results Patients ( n = 76) were divided according to apnea-hypopnea-index in absent-mild (AM) OSA group (< 15events/h, n = 30) and moderate-severe (MS) OSA group (≥ 15events/h, n = 46). At the end of the study both groups showed similar weight loss (3.2 ± 2.3 vs. 3.0 ± 2.7%, p = 0.898). Only AM group showed a significant increase in the RR interval (879 ± 118 vs. 948 ± 130 ms, p = 0.016) and in cutaneous vascular conductance post-occlusive reactive hyperemia (1.17 ± 0.23 vs. 1.27 ± 0.20 APU/mmHg, p = 0.033), decrease in central systolic pressure (113 ± 12 vs. 107 ± 9 mmHg, p = 0.006) and in pulse wave velocity (PWV, 6.9 ± 0.6 vs. 6.7 ± 0.6 m/s, p = 0.004). Conclusions After short term of nutritional intervention, individuals with obesity had modest weight loss regardless of OSA severity but vascular outcomes were improved primarily in the absence of moderate or severe OSA.
Morphological and functional properties of vascular stiffness (intima-media thickness, instantaneous diameter, pulse wave velocity, blood pressure) could be monitored solely using ultrasound. Yet, few ultrasound studies estimate both pulse wave velocity and blood pressure. This study presents an in vitro evaluation of a dual-site ultrasound system for the simultaneous estimation of pulse wave velocity and blood pressure from radio-frequency ultrasound data. The circulatory mock-loop incorporating an arm phantom was used as a controlled test environment. Reference pressure and pulse wave velocity values were obtained via a commercial pressure sensor and the PulsePen device (DiaTecne s.r.l., Milano, Italy), respectively. The custom dual-site ultrasound system (6 cm distance between probes) was evaluated across pressures ranging from hypotension to hypertensive crisis. To assess the most accurate estimation strategy, pulse wave velocity was estimated using multiple signal processing approaches, including derivative-based, pulse-feature, cross-correlation, and tangent intersection methods, while blood pressure was derived from linear, exponential, and logarithmic models relating diameter waveforms to pressure. The in vitro mock-loop was improved using a viscous glycerol solution as a blood-mimicking fluid instead of deionized water. The tangent intersection method yielded pulse wave velocity values most consistent with the tonometric reference (0.3 m/s mean error). For blood pressure estimation, the linear equation achieved the best performance, with − 1.8 ± 1.1 mmHg systolic blood pressure mean difference to the reference. Using 40 wt
