Ventura-Antunes L, Nackenoff A, Romero-Fernandez W, Wang Y, Bosworth AM, Prusky A, Wang E, Carvajal-Tapia C, Shostak A, Harmsen H, Mobley B, Maldonado J, Womble N, Solopova E, Snider JC, Merryman WD, Lippmann ES, Schrag M. Arteriolar degeneration and stiffness in cerebral amyloid angiopathy are linked to Aβ deposition and lysyl oxidase. Alzheimers Dement 2025;21(6):e70254. doi: 10.1002/alz.70254. 

 

Background: Cerebral amyloid angiopathy (CAA) is characterized by amyloid beta (Aβ) accumulation in cerebral vessel walls, leading to vascular degeneration, fragility and hemorrhage. Despite its frequent coexistence with Alzheimer’s disease, the mechanisms underlying arteriolar degeneration and stiffness in CAA remain poorly defined. Vascular smooth muscle cell (VSMC) loss and extracellular matrix remodeling have been implicated, but the contributions of Aβ and cross-linking enzymes such as lysyl oxidase (LOX) are unclear. 

 

Hypothesis: This study hypothesized that vascular degeneration and stiffness in CAA are associated with Aβ deposition and increased LOX activity in cerebral arterioles. 

 

Methods: The authors analyzed post mortem cortical tissue from 26 individuals with and without CAA using optical clearing, immunostaining and light sheet fluorescence microscopy. Vascular morphology was reconstructed with IMARIS, and vessel geometry quantified using Vesselucida 360 and Vesselucida Explorer. Arteriolar stiffness was measured via atomic force microscopy, and correlations among Aβ, LOX and morphological changes were assessed statistically. 

 

Results: CAA vessels showed a 55% reduction in VSMC volume and up to 300% greater stiffness than controls. Arteriolar dilation, irregular diameters and rupture correlated with increasing Aβ and LOX deposition, while tortuosity peaked early in disease. LOX volume strongly correlated with Aβ load and inversely with VSMC content. 

 

Conclusions: CAA arteriolar degeneration is marked by VSMC loss, vessel stiffening and elevated LOX linked to Aβ deposition. Restoring extracellular matrix integrity may represent a therapeutic target for vascular dysfunction in CAA. 

Gama Sosa MA, De Gasperi R, Pryor D, Perez Garcia GS, Perez GM, Abutarboush R, Kawoos U, Hogg S, Ache B, Sowa A, Tetreault T, Varghese M, Cook DG, Zhu CW, Tappan SJ, Janssen WGM, Hof PR, Ahlers ST, Elder GA. Late chronic local inflammation, synaptic alterations, vascular remodeling and arteriovenous malformations in the brains of male rats exposed to repetitive low-level blast overpressures. Acta Neuropathol Commun 2023;11(1):81. doi: 10.1186/s40478-023-01553-6. 

 

Background: Repetitive low-level blast exposure has been linked to long-term neurological and vascular damage contributing to behavioral and cognitive deficits resembling post-traumatic stress disorder. Previous work identified vascular degeneration and inflammation as major factors in blast-induced brain injury, but the chronic neuropathological consequences remained unclear. 

 

Hypothesis: This study hypothesized that repetitive low-level blast exposure produces delayed vascular degeneration leading to chronic neuroinflammation, synaptic alterations and the development of vascular malformations. 

 

Methods: The authors exposed male rats to three 74.5-kPa blasts and examined their brains 13 months later. Vascular networks were reconstructed and quantified using micro-CT with Vesselucida 360 and Vesselucida Explorer. Histology, immunohistochemistry, electron microscopy and Western blotting assessed inflammation, vascular remodeling and synaptic proteins. 

 

Results: Blast-exposed rats exhibited late perivascular inflammation, apoptotic microglia and astrocytes, and vascular constriction with reduced hippocampal vessel length, diameter and volume. These regions showed neuronal loss, dendritic degeneration and degradation of vascular extracellular matrix. Synaptic proteins PSD95, spinophilin and synaptophysin were significantly decreased. Arteriovenous malformations and vascular tortuosity developed near cortical tears, indicating shear-related remodeling. 

 

Conclusions: Chronic blast exposure causes progressive neurovascular injury characterized by inflammation, synaptic loss and vascular malformations, implicating delayed vascular remodeling as a key mechanism in long-term blast-related neuropathology. 

Yao Y, Taub AB, LeSauter J, Silver R. Identification of the suprachiasmatic nucleus venous portal system in the mammalian brain. Nat Commun 2021;12(1):5643. doi: 10.1038/s41467-021-25793-z.

 

Background: The suprachiasmatic nucleus (SCN) of the hypothalamus acts as the brain’s circadian clock, coordinating daily physiological rhythms. While the pituitary portal system has been the only known vascular portal pathway in the mammalian brain, the mechanisms by which SCN neurosecretions reach their targets remained unclear. Understanding whether specialized vascular routes exist for SCN signaling could reveal novel modes of brain communication.

 

Hypothesis: This study hypothesized that a portal vascular system links the SCN to a nearby circumventricular organ, the organum vasculosum of the lamina terminalis (OVLT), allowing efficient transfer of SCN-derived humoral signals without dilution in systemic circulation.

 

Methods: The authors examined adult mouse brains using tissue clearing with an iDISCO protocol, triple-label immunostaining for arginine vasopressin, collagen and smooth muscle actin, and light-sheet microscopy. Three-dimensional image processing and tracing of capillary networks were performed using Imaris and Vesselucida 360, with quantitative vascular analyses carried out in Vesselucida Explorer.

 

Results: High-resolution imaging revealed continuous portal capillaries connecting the rostral tip of the SCN to the ventral superficial plexus of the OVLT, coursing along the floor of the third ventricle. The SCN shell exhibited a significantly denser and more complex vasculature than the core (8.7 × 10^-6 vs. 4.6 × 10^-6 nodes/µm³, p < 0.001). These vessels were distinct from lateral hypothalamic veins and comparable in structure to the hypophyseal portal system.

 

Conclusions: The findings identify a second venous portal system in the mammalian brain connecting the SCN and OVLT, suggesting a direct vascular route for circadian signals and redefining pathways of neurovascular communication.

Jacobsen NL, Norton CE, Shaw RL, Cornelison DDW, Segal SS. Myofibre injury induces capillary disruption and regeneration of disorganized microvascular networks. J Physiol 2022;600(1):41-60. doi: 10.1113/JP282292.

 

Background: Skeletal muscle regeneration depends not only on the restoration of myofibres but also on the recovery of an intact microvascular network. While myofibre regeneration is well characterized, the processes by which capillaries and other microvessels are disrupted and reformed after injury remain poorly understood. The study investigated how microvascular structure and function change following skeletal muscle injury induced by barium chloride (BaCl₂).

 

Hypothesis: This study hypothesized that BaCl₂-induced skeletal muscle injury leads to microvascular disruption as a secondary effect of myofibre degeneration rather than direct cytotoxicity to endothelial or smooth muscle cells, and that regenerating capillary networks initially form in a disorganized manner before remodeling as myofibres mature.

 

Methods: The authors examined microvascular injury and regeneration in the gluteus maximus muscle of mice after BaCl₂ injection. Ex vivo assays using isolated microvessels and endothelial tubes assessed membrane potential, calcium dynamics and cell viability. Confocal microscopy and three-dimensional reconstructions of resistance networks were performed using Vesselucida and Vesselucida Explorer to quantify vessel number, diameter and anastomoses.

 

Results: BaCl₂ depolarized microvascular smooth muscle and endothelial cells and increased smooth muscle calcium but did not cause their death. In vivo, capillaries fragmented within one day post-injury, whereas arterioles and venules remained intact. Capillary networks regenerated by five days post-injury but were dilated, misaligned with myofibres and associated with increased terminal arterioles. By twenty-one days, capillary orientation and microvascular unit organization were restored to normal.

 

Conclusions: The findings demonstrate that capillary loss follows myofibre degeneration and that regenerating microvessels initially form disorganized, hyperdilated networks that progressively remodel into functional microvascular units as skeletal muscle regenerates.

Alese OM, Wilson AC, Tessier KM, Loavenbruck A, Dedeker C, Lassig AA. Characterization of cutaneous microvasculature using 3D imaging: A feasibility study in a cohort of head and neck surgery patients with attention to smoking status. JPRAS Open 2025;44:493-505. doi: 10.1016/j.jpra.2025.03.020.

 

Background: This study aimed to evaluate a novel three-dimensional imaging method to characterize cutaneous microvasculature in patients undergoing major head and neck surgery and to examine associations between baseline vascular morphology and post-operative wound healing outcomes. Understanding how vascular structure relates to healing could improve prediction and management of surgical recovery.

 

Hypothesis: This study hypothesized that specific morphological features of the cutaneous microvasculature, quantified through three-dimensional imaging, are associated with poorer wound healing outcomes following surgery.

 

Methods: The authors prospectively enrolled 17 adult patients undergoing major head and neck surgery. Full-thickness neck flap biopsies were immunostained for collagen IV and imaged using confocal microscopy. The authors analyzed vessel morphology by tracing three-dimensional reconstructions with Vesselucida 360, quantifying parameters such as isolated elements, branching nodes, endings, loops, total length, surface area and volume. Vesselucida Explorer was used to extract and analyze quantitative vascular metrics. Statistical analyses were performed using R version 3.6.1 and SAS version 9.4, with significance set at p < 0.05.

 

Results: Males and patients with prior chemotherapy showed higher isolated elements. Current and former smokers exhibited more tortuous and irregular vessels than never-smokers. Increased isolated elements were significantly associated with wound complications, long-term wound care and re-hospitalization. VEGF-A correlated positively with vessel endings and surface area, and PLGF correlated with isolated elements.

 

Conclusions: The study demonstrated that increased isolated vascular elements correlate with poorer wound healing, supporting three-dimensional vascular analysis as a promising predictive tool.

Brady EL, Prado O, Johansson F, Mitchell SN, Martinson AM, Karbassi E, Reinecke H, Murry CE, Davis J, Stevens KR. Engineered tissue vascularization and engraftment depends on host model. Sci Rep 202;13(1):1973. doi: 10.1038/s41598-022-23895-2.

 

Background: Developing engineered tissues that integrate with host vasculature is a key challenge in regenerative medicine. Previous studies have focused on constructing human vascular networks within engineered tissues before implantation, yet the influence of the host environment on graft vascularization and cell survival remains underexplored. Understanding how host species and implant site affect vascular integration is essential for improving the reproducibility and efficacy of engineered tissue engraftment.

 

Hypothesis: This study hypothesized that the host animal model and anatomic implant location critically determine vascularization and cardiomyocyte engraftment outcomes in human engineered tissues implanted in vivo.

 

Methods: The authors fabricated fibrin-based tissues containing patterned endothelial “cords” and cardiomyocytes, implanted them on the heart or in the abdomen of athymic nude mice and rats, and analyzed explants using histology and immunostaining. Vessel morphology was quantified from 3D confocal images using Vesselucida, with vessel diameter and geometry analyzed via Vesselucida Explorer.

 

Results: In mice, endothelial cords guided the formation of patterned, blood-filled vessels with larger lumens and minimal inflammation in both abdominal and epicardial sites. In contrast, rat implants showed pronounced inflammation, collagen deposition and loss of vascular patterning. Despite disrupted vessel organization, rats exhibited over threefold larger human cardiomyocyte grafts than mice.

 

Conclusions: Host biology strongly influences engineered tissue vascularization and engraftment, demonstrating that vascular and cardiac integration require distinct host conditions, with significant implications for translational tissue engineering.

Fopiano KA, Zhazykbayeva S, El-Battrawy I, Buncha V, Pearson WM, Hardell DJ, Lang L, Hamdani N, Bagi Z. PDE9A inhibition improves coronary microvascular rarefaction and left ventricular diastolic dysfunction in the ZSF1 rat model of HFpEF. Microcirculation 2024;31(8):e12888. doi: 10.1111/micc.12888.

 

Background: Heart failure with preserved ejection fraction (HFpEF) is frequently driven by comorbidities such as hypertension, obesity and diabetes, leading to left ventricular (LV) diastolic dysfunction associated with coronary microvascular disease. Excessive oxidative stress and reduced nitric oxide availability contribute to vascular dysfunction and microvascular rarefaction. Phosphodiesterase 9A (PDE9A) has been implicated in HFpEF pathogenesis, and its inhibition may improve cardiac and vascular outcomes by restoring cGMP signaling.

 

Hypothesis: This study hypothesized that inhibition of PDE9A would attenuate coronary microvascular rarefaction and improve LV diastolic dysfunction in the ZSF1 rat model of HFpEF through mechanisms involving reduced oxidative stress and enhanced antioxidant defense.

 

Methods: The authors used obese ZSF1 rats treated for two weeks with the PDE9A inhibitor PF04447943 or vehicle. Echocardiography was performed to assess LV function, and coronary microvascular networks were reconstructed in three dimensions using Vesselucida and analyzed with Vesselucida Explorer. Oxidative and nitrosative stress markers, proteomic profiles and antioxidant protein levels were quantified by biochemical assays, liquid chromatography–mass spectrometry and western blotting.

 

Results: PDE9A inhibition improved LV diastolic function without affecting systolic performance or hypertrophy. It mitigated coronary microvascular rarefaction by increasing the number of branching nodes, decreased myocardial hydrogen peroxide and 3-nitrotyrosine levels, and upregulated peroxiredoxin-5 expression identified through proteomic and immunoblot analyses.

 

Conclusions: PDE9A inhibition ameliorated coronary microvascular rarefaction and LV diastolic dysfunction in HFpEF rats, likely through enhancement of peroxiredoxin-dependent antioxidant mechanisms, suggesting a potential therapeutic strategy for cardiometabolic heart failure.

Button EB, Boyce GK, Wilkinson A, Stukas S, Hayat A, Fan J, Wadsworth BJ, Robert J, Martens KM, Wellington CL. ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice. Alzheimers Res Ther 2019;11(1):44. doi: 10.1186/s13195-019-0497-9.

 

Background: Alzheimer’s disease (AD) is marked by amyloid-β (Aβ) plaques, neurofibrillary tangles and neurodegeneration, with many patients also showing cerebrovascular amyloid deposition known as cerebral amyloid angiopathy (CAA). Circulating high-density lipoproteins (HDL) and their major protein component apolipoprotein A-I (apoA-I) exert vasoprotective effects and have been associated with reduced AD risk and amyloid burden in experimental models.

 

Hypothesis: This study hypothesized that deficiency of apoA-I exacerbates amyloid deposition, cerebrovascular pathology and astrocyte reactivity in APP/PS1 transgenic mice.

 

Methods: The authors used APP/PS1 mice either hemizygous or deficient for apoA-I. Plasma lipids, Aβ levels and markers of inflammation were measured by ELISA and qRT-PCR. Immunofluorescence was used to quantify amyloid, vascular and astrocytic markers. Vascular morphology, including vessel diameter and tortuosity, was analyzed using Vesselucida 360 and data were reconstructed and quantified with Vesselucida Explorer. Behavioral performance was assessed by contextual and cued fear conditioning.

 

Results: ApoA-I deficiency significantly increased total and vascular Aβ deposition in the cortex, elevated cortical Il1b mRNA, ICAM-1, PDGFRβ and GFAP protein levels, and intensified astrocyte reactivity around Aβ-laden vessels and plaques. No effects on hippocampal amyloid or behavior were observed.

 

Conclusions: Loss of apoA-I amplifies cortical amyloid accumulation and cerebrovascular astrogliosis in APP/PS1 mice, supporting a protective role of apoA-I–containing HDL against amyloid pathology and astrocyte activation in AD.