Current Issue Highlights

Upregulation of CXCL10/CXCR3 Axis Induced by Pulmonary Hemodynamic Stress Promotes Vascular Remodeling in Chronic Thromboembolic Pulmonary Hypertension
April 22, 2026: 83(7):e24619
BACKGROUND:
Perivascular inflammation induced by abnormal hemodynamic stress is increasingly recognized as a key driver of secondary microvasculopathy in chronic thromboembolic pulmonary hypertension. Although circulating CXCL10 (C-X-C motif chemokine ligand 10) is elevated in chronic thromboembolic pulmonary hypertension and correlates with pulmonary hemodynamics, its mechanistic contribution to vascular remodeling remains unclear.
METHODS:
Experiments were performed using pulmonary endarterectomy specimens from patients with chronic thromboembolic pulmonary hypertension and a left pulmonary artery ligation rat model.
RESULTS:
In pulmonary endarterectomy specimens, CXCL10 was predominantly localized to CD68+ mannose receptor C-type 1+ macrophages, whereas CXCR3 (C-X-C motif chemokine receptor 3) was broadly expressed in the vascular wall and enriched in distal nonoccluded pulmonary arteries with increased mannose receptor C-type 1+ macrophage accumulation. In left pulmonary artery ligation rats, pulmonary hypertension and vascular remodeling were accompanied by perivascular accumulation of CXCL10+CXCR3+ mannose receptor C-type 1+ macrophages, increased plasma CXCL10, and upregulation of CXCL10 and CXCR3 in the right lung. CXCR3 expression was also increased in pulmonary arterial smooth muscle cells (PASMCs), and CXCL10 directly promoted proliferation of left pulmonary artery ligation-derived PASMCs in a CXCR3-dependent manner. In parallel, CXCL10 drove macrophages toward a proinflammatory, pro-proliferative secretory phenotype, and conditioned medium from macrophages enhanced PASMC proliferation. Pharmacological CXCR3 inhibition with AMG487 attenuated pulmonary hypertension, vascular remodeling, PASMC proliferation, and perivascular macrophage accumulation in both preventive and therapeutic settings. Similarly, cell type-specific CXCR3 knockdown in smooth muscle cells or macrophages ameliorated left pulmonary artery ligation-induced pulmonary hypertension, vascular remodeling, and associated perivascular inflammation.
CONCLUSIONS:
The CXCL10/CXCR3 axis links hemodynamic stress to pulmonary vascular remodeling in chronic thromboembolic pulmonary hypertension by coordinating PASMC hyperproliferation and macrophage-driven inflammation, and may represent a therapeutic target.
Salusin-α Restores Vascular Relaxation and Remodeling in Pulmonary Hypertension
April 10, 2026: 83(7):e25722
BACKGROUND:
A hallmark of pulmonary hypertension (PH) is the progressive increase in pulmonary arterial resistance caused by impaired pulmonary artery (PA) relaxation and vascular remodeling. Salusin-α, a cardiovascular-active peptide, has been implicated in several cardiovascular diseases; however, its role in PH remains undefined.
METHODS:
PAs were isolated from rats for isometric tension recording to assess relaxation. PA remodeling was quantified using histological morphometric analysis. Right ventricular pressure and hypertrophy were measured to evaluate PH severity.
RESULTS:
Salusin-α levels were significantly decreased in both plasma and PAs from PH rats compared with controls. Both acute and chronic salusin-α administration improved endothelium-dependent and -independent PA relaxation, increased endothelial nitric oxide synthase activity and nitric oxide levels in PA endothelial cells, enhanced Nrf2 (nuclear factor erythroid 2-related factor 2) and superoxide dismutase expression and activity in PA smooth muscle cells, and decreased NAD(P)H oxidase expression, activity, and reactive oxygen species levels. Salusin-α also inhibited PA smooth muscle cell proliferation and migration, attenuated pulmonary vascular remodeling, and decreased right ventricular pressure, hypertrophy, and mortality in PH rats. Neutralizing endogenous salusin-α exerted opposite effects. Pharmacological inhibition demonstrated that endothelial nitric oxide synthase and superoxide dismutase contributed to the protective actions of salusin-α, whereas NAD(P)H oxidase inhibition or reactive oxygen species scavenging prevented the effects of salusin-α neutralization.
CONCLUSIONS:
Salusin-α improves endothelium-dependent vasodilation via endothelial nitric oxide synthase mediated nitric oxide release in PA endothelial cells, and promotes endothelium-independent vasodilation while attenuating pulmonary vascular remodeling via inhibition of NAD(P)H oxidase-reactive oxygen species signaling and activation of the Nrf2/superoxide dismutase signaling. Restoring reduced salusin-α may present a novel therapeutic strategy for PH treatment.
Initiating Events of Retinopathy in Spontaneously Hypertensive Rats: Microvascular Rarefaction and Functional Deficits
April 08, 2026: 83(7):e26116
BACKGROUND:
Target organ damage is crucial for hypertension risk stratification. However, the lack of sensitive assessment tools for early target organ damage in the presence of elevated blood pressure limits timely intervention. This study used the retina to investigate subclinical neurovascular damage and identify early imaging biomarkers.
METHODS:
We monitored male spontaneously hypertensive rats and Wistar-Kyoto controls weekly from 4 to 9 weeks of age. Weekly assessments included noninvasive blood pressure and multimodal fundus imaging, including optical coherence tomography, optical coherence tomography angiography and electroretinography. Histological analyses and fluorescein fundus angiography validated structural microvascular changes and blood-retinal barrier integrity.
RESULTS:
The blood pressure of spontaneously hypertensive rats increased significantly from 5 weeks of age (P<0.05). At the prehypertensive stage (6 weeks), spontaneously hypertensive rats exhibited decreased superficial vascular plexus density and reduced scotopic electroretinography b-wave amplitude. Fluorescein fundus angiography demonstrated that the blood-retinal barrier remained functionally intact without leakage at this stage. These microvascular and functional deficits preceded structural changes on optical coherence tomography. Subsequently, vascular damage progressed to deeper plexuses, accompanied by inner retinal thinning, apoptosis, and continued functional decline. Linear mixed-effects modeling confirmed a negative correlation between the prehypertensive stage and decreased superficial vascular density (P<0.001).
CONCLUSIONS:
In spontaneously hypertensive rats, superficial microvascular rarefaction and inner retinal dysfunction represent the initiating pathological events, preceding blood-retinal barrier breakdown and macrovascular remodeling. Optical coherence tomography angiography-quantified superficial vascular plexus density is a sensitive and objective imaging biomarker for assessing retinal damage during the prehypertensive stage, which significantly precedes macrovascular signs.
Vascular Sphingosine Kinase 1 Regulates Angiotensin II–Induced Hypertension
April 07, 2026: 83(7):e25480
BACKGROUND:
S1P (sphingosine-1-phosphate) signaling plays a key role in regulating the cardiovascular system. In experimental essential hypertension (HTN), expression of Sphk1 (sphingosine kinase 1), a key S1P-producing enzyme, is upregulated in the vasculature. Mice with global Sphk1 deletion exhibit alleviated AngII (angiotensin II)-induced HTN. However, cellular mechanisms underlying this protective effect remain unclear due to pleiotropic S1P actions.
METHODS:
Mice with targeted deletion of Sphk1 in smooth muscle cells (SMCs) or endothelial cells were generated using the Cre-loxP system. To induce HTN, mice were infused with AngII (490 ng/min per kilogram for 14 days), using osmotic minipumps. Blood pressure was monitored, and vascular structure and function were assessed ex vivo using wire/pressure myography and histological analysis. To identify mechanistic pathways, RNA sequencing was performed on mouse aortas and mesenteric arteries, followed by Gene Set Enrichment Analysis and validation by RT-qPCR/Western blotting.
RESULTS:
SMC-specific deletion of Sphk1 conferred significant protection against HTN (mean systolic blood pressure±SD, 131.5±14.6 versus 168.3±14.3 mm Hg in WT^f/f control, P<0.05). Endothelial cell–specific Sphk1 knockout developed HTN comparable to WT^f/f. Reduced systolic blood pressure in AngII-infused SMC knockout-Sphk1 was linked to reduced myogenic tone and decreased expression of Rock1/2 (Rho-associated protein kinase 1 and 2) in mesenteric arteries. Despite protection from HTN, mesenteric arteries of AngII-infused SMC knockout-Sphk1 mice were stiffer and exhibited impaired vasorelaxation, associated with excessive Fn1 (fibronectin 1) deposition. An inverse correlation between FN1 and SPHK1 protein expression was also observed in human arteries. Notably, these arterial alterations were absent in normotensive SMC knockout-Sphk1 mice.
CONCLUSIONS:
SMC-derived Sphk1 plays a predominant role in AngII-induced HTN by modulating myogenic tone.
Hypertension Drives Protein Lactylation and Vascular Dysfunction in Skeletal Muscle
April 22, 2026: 83(7):e25665
BACKGROUND:
Emerging evidence suggests a critical interplay between skeletal muscle metabolism and vascular function in the context of hypertension. Elevated plasma lactate levels precede the onset of hypertension and are inversely associated with skeletal muscle mass, highlighting skeletal muscle atrophy and metabolic dysregulation as key contributors to cardiovascular dysfunction.
METHODS:
Male and female Wistar rats and spontaneously hypertensive rats were studied. Skeletal muscle performance was evaluated using in vivo plantarflexion torque measurements. Femoral arteries with surrounding skeletal muscle were isolated to assess contractility and relaxation. Plasma and muscle lactate levels were quantified using colorimetric assays. Structural remodeling and mitochondrial function were assessed via wheat germ agglutinin staining, succinate dehydrogenase activity, and high-resolution respirometry. Protein lactylation was evaluated by mass spectrometry-based lactylated proteomics. Human translational relevance was examined using publicly available skeletal muscle transcriptomic data
RESULTS:
Spontaneously hypertensive rats exhibited skeletal muscle dysfunction marked by increased fatigability, reduced muscle mass, impaired mitochondrial activity, and elevated muscle lactate levels. Despite upregulation of oxidative markers, persistent lactate accumulation suggested a maladaptive metabolic shift. Proteomics revealed differential lactylation of key structural proteins (myosins, nebulin) and metabolic enzymes (Nampt, GAPDH [glyceraldehyde-3-phosphate dehydrogenase]). The anticontractile effect of skeletal muscle on femoral arteries was completely lost in spontaneously hypertensive rats, accompanied by impaired vascular relaxation and increased arterial lactylation. Human transcriptomic data supported parallel metabolic alterations in hypertension.
CONCLUSIONS:
Hypertension disrupts skeletal muscle metabolic homeostasis and muscle-vascular communication, driven in part by persistent lactate accumulation and altered protein lactylation. Targeting lactate-mediated signaling may offer new therapeutic avenues for hypertensive vascular dysfunction.

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Hypertension Treatment Intentions: A Health Belief Model Analysis
Hypertension. July 02, 2026
Brain Iron in Nucleus Accumbens and Cognitive Function in Preeclampsia
Hypertension. July 02, 2026
BACKGROUND:
Preeclampsia is associated with long-term cognitive dysfunction, potentially linked to cerebral iron deposition. This study investigated striatal iron alterations using quantitative susceptibility mapping and their relationship with cognitive function in patients with preeclampsia.
METHODS:
This cross-sectional study enrolled 321 participants, including nonpregnant and pregnant healthy controls, and patients with preeclampsia. Participants underwent the Montreal Cognitive Assessment, Trail Making Test, and 1.5 T brain magnetic resonance imaging. Striatal iron content was quantified using quantitative susceptibility mapping reconstructed with a morphology-enabled dipole inversion algorithm.
RESULTS:
Preeclampsia patients showed poorer executive function (Trail Making Test part [A+B]: partial η²=0.170; part B: partial η²=0.100) and elevated nucleus accumbens magnetic susceptibility (all P<0.001). Age (β=0.744, P<0.001) and hematocrit (β=0.846, P=0.011) were independently associated with iron levels. In addition, significant interactions between nucleus accumbens susceptibility values and preeclampsia status were observed for log-transformed Trail Making Test completion times (part [A+B]: interaction β=0.388, P=0.006; part B: interaction β=0.424, P=0.003), indicating that elevated iron specifically exacerbates executive vulnerability in preeclampsia.
CONCLUSIONS:
Nucleus accumbens iron level is elevated in preeclampsia and correlates with executive performance. Although the cross-sectional design limits causal conclusions, these findings highlight nucleus accumbens iron deposition as a key pathological feature underlying preeclampsia-related cerebral involvement.
Changes in Retinal Microvasculature During Healthy Pregnancy Measured by AO
Hypertension. June 29, 2026
BACKGROUND:
Adaptive optics retinal imaging (rtx1e, Imagine Eyes, Orsay, France) enables high-resolution visualization of the retinal microvasculature, providing insights into systemic vascular health. Currently, no studies exist describing changes in wall-to-lumen ratio (WLR) during pregnancy, neither during the physiological course of pregnancy nor in pregnancy-associated complications.
METHODS:
This single-center, prospective study at the Leipzig University Hospital, Germany, examines changes in retinal microvasculature by employing adaptive optics to calculate the WLR of an arteriole within a few seconds. The study examined a well-phenotyped cohort of 460 primarily White healthy singleton pregnancies, with 543 measurements taken from the first to the third trimester. The WLR was automatically determined using the nnUNet deep learning model.
RESULTS:
Step-down selection mixed-effects modeling identified gestational week, maternal age, mean arterial pressure, and parity as significant contributors to WLR, whereas body mass index did not improve model fit. In the final model, advancing gestational week (P<0.001), higher maternal age (0.012), and higher mean arterial pressure (<0.001) were independently associated with increased WLR, whereas multiparous women showed significantly lower WLR values compared with nulliparous women, with negligible multicollinearity (variance inflation factor ≈1).
CONCLUSIONS:
We identify WLR as a sensitive marker for imaging microvascular remodeling, serving as an indicator of adaptation to physiological pregnancy. Normal pregnancy is associated with an instant change of the retinal microvasculature indicated by an increase of WLR. Further studies are required to investigate the postpartum course of WLR and establish whether these changes are reversible.
REGISTRATION:
URL: https://www.drks.de; Unique identifier: DRKS00032530.