Mechanisms Underlying Vascular Endothelial Growth Factor Receptor Inhibition–Induced Hypertension

Drugs targeting the VEGF (vascular endothelial growth factor) signaling pathway are approved for several malignancies. Unfortunately, VEGF inhibitors lead to hypertension in 30% to 80% patients. Reduced nitric oxide synthase activity, microvascular rarefaction, and increased vascular resistance have been proposed as potential mechanisms. We aimed to assess these mechanisms in patients receiving the VEGF inhibitor, pazopanib, for cancer. Twenty-seven normotensive patients with advanced solid malignancies received pazopanib 800 mg od. Endothelial function was assessed using forearm plethysmography with intraarterial infusions of acetylcholine. Detailed hemodynamic measurements were taken. Density and diameter of the conjunctival and episcleral microvasculature were evaluated using hemoglobin video imaging. Measurements were taken at baseline, 2, and 12 weeks after initiation of pazopanib or earlier if patients became hypertensive. By the end of the trial, systolic blood pressure increased by 12 mm Hg (95% CI, 4–19 mm Hg; P =0.003), diastolic by 10 mm Hg (95% CI, 5–15 mm Hg; P <0.001), and peripheral vascular resistance by 888 dynes×s/cm 5 (95% CI, 616–1168 dynes×s/cm 5 ; P <0.001). Forearm blood flow improved: Ratio of acetylcholine response at end of trial/baseline was 2.8 (95% CI, 1.84–4.25; P <0.001). Microvascular density in the sclera was reduced by −15.5% (95% CI, −25.7% to −5.3%; P =0.003) and diameter by −2.09 µm (95% CI, −3.95 to −0.19 µm; P =0.03). A post hoc colorimetric assay revealed that pazopanib inhibited acetylcholinesterase activity by −56% (95% CI, −62% to −52%; P <0.001). Unexpectedly, pazopanib led to an increase in acetylcholine-mediated forearm blood flow response, likely due to the inhibition of acetylcholinesterase activity. Pazopanib increased peripheral vascular resistance and reduced microvascular density and diameter, suggesting that microvascular rarefaction could be one of the key mechanisms behind VEGF inhibition–induced hypertension. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01392352.

Promotion of Aerobic Exercise Induced Angiogenesis Is Associated With Decline in Blood Pressure in Hypertension

Microvascular rarefaction plays a key role in hypertension-induced microvascular organ damage. Aerobic exercise (AE) can reduce blood pressure and improve endothelial progenitor cell (EPC) function in hypertension. Here, we investigate the effect of AE on hypertensive microvascular rarefaction and its association with the improvement of EPCs angiogenic capacity and blood pressure decline. One hundred forty-one patients with essential hypertension without any antihypertension medication were randomized into AE group (n=75) and control group (n=66). AE was performed for 5 days a week and 12 weeks in total using cycle ergometer with moderate intensity. Hypertensive subjects displayed decreased skin capillary density, retinal capillary density, and increased retinal nonperfused area, which were related to blood pressure. AE markedly increased capillary density skin capillary density: (43.14±4.66)/mm 2 versus (39.86±4.92)/mm 2 , P <0.001; retinal capillary density: (54.51±2.35)% versus (52.85±2.9)%, P <0.001; and decreased the nonperfused area (0.09±0.07) mm 2 versus (0.12±0.07) mm 2 , P <0.01, which was accompanied with the increased angiogenic capacity of EPCs. Interestingly, AE significantly reduced systolic blood pressure ( P <0.01), which was independently correlated with skin capillary density (β=−0.47, t =−3.06, P =0.004) and retinal capillary density (β=−0.46, t =−3.01, P =0.005). Furthermore, AE accelerated EPC angiogenic ability via inhibiting NOTCH 1 expression and elevating its downstream Akt/eNOS (endothelial nitric oxide synthase) signaling in hypertension. Blockage of NOTCH 1/Akt/eNOS signaling almost completely abolished the protective effect of AE on EPC function. The current study demonstrates for the first time that AE can lower blood pressure and reduce microvascular rarefaction in hypertension, which is partially due to restoration of angiogenesis capacity of EPCs via NOTCH 1/Akt/eNOS signaling pathway.

Acute Kidney Injury, Microvascular Rarefaction, and Estimated Glomerular Filtration Rate in Kidney Transplant Recipients

Background and objectivesAnimal studies suggest that microvascular rarefaction is a key factor in the acute kidney disease to CKD transition. Hence, delayed graft function appears as a unique human model of AKI to further explore the role of microvascular rarefaction in kidney transplant recipients. Here, we assessed whether delayed graft function is associated with peritubular capillary loss and evaluated the association between this loss and long-term kidney graft function.Design, setting, participants, & measurementsThis observational, retrospective cohort study included 61 participants who experienced delayed graft function and 130 who had immediate graft function. We used linear regression models to evaluate associations between delayed graft function and peritubular capillary density expressed as the percentage of efficient cortical area occupied by peritubular capillaries in pre- and post-transplant graft biopsies. eGFRs 1 and 3 years post-transplant were secondary outcomes.ResultsPost-transplant biopsies were performed at a median of 113 days (interquartile range, 101–128) after transplantation. Peritubular capillary density went from 15.4% to 11.5% in patients with delayed graft function (median change, −3.7%; interquartile range, −6.6% to −0.8%) and from 19.7% to 15.1% in those with immediate graft function (median change, −4.5%; interquartile range, −8.0% to −0.8%). Although the unadjusted change in peritubular capillary density was similar between patients with and without delayed graft function, delayed graft function was associated with more peritubular capillary loss in the multivariable analysis (adjusted difference in change, −2.9%; 95% confidence interval, −4.0 to −1.8). Pretransplant peritubular capillary density and change in peritubular capillary density were associated with eGFR 1 and 3 years post-transplantation.ConclusionsPerioperative AKI is associated with lower density in peritubular capillaries before transplantation and with loss of peritubular capillaries following transplantation. Lower peritubular capillary density is linked to lower long-term eGFR.

Obesity-induced Cognitive Impairment in Older Adults: a Microvascular Perspective

Over two thirds of individuals aged 65 and older are obese or overweight in the United States. Epidemiological data show an association between the degree of adiposity and cognitive dysfunction in the elderly. In this review, the pathophysiological roles of microvascular mechanisms, including impaired endothelial function and neurovascular coupling responses, microvascular rarefaction and blood-brain barrier disruption in the genesis of cognitive impairment in geriatric obesity are considered. The potential contribution of adipose-derived factors and fundamental cellular and molecular mechanisms of senescence to exacerbated obesity-induced cerebromicrovascular impairment and cognitive decline in aging are discussed.

Microvascular disease in chronic kidney disease: the base of the iceberg in cardiovascular comorbidity

Chronic kidney disease (CKD) is a relentlessly progressive disease with a very high mortality mainly due to cardiovascular complications. Endothelial dysfunction is well documented in CKD and permanent loss of endothelial homeostasis leads to progressive organ damage. Most of the vast endothelial surface area is part of the microcirculation, but most research in CKD-related cardiovascular disease (CVD) has been devoted to macrovascular complications. We have reviewed all publications evaluating structure and function of the microcirculation in humans with CKD and animals with experimental CKD. Microvascular rarefaction, defined as a loss of perfused microvessels resulting in a significant decrease in microvascular density, is a quintessential finding in these studies. The median microvascular density was reduced by 29% in skeletal muscle and 24% in the heart in animal models of CKD and by 32% in human biopsy, autopsy and imaging studies. CKD induces rarefaction due to the loss of coherent vessel systems distal to the level of smaller arterioles, generating a typical heterogeneous pattern with avascular patches, resulting in a dysfunctional endothelium with diminished perfusion, shunting and tissue hypoxia. Endothelial cell apoptosis, hypertension, multiple metabolic, endocrine and immune disturbances of the uremic milieu and specifically, a dysregulated angiogenesis, all contribute to the multifactorial pathogenesis. By setting the stage for the development of tissue fibrosis and end organ failure, microvascular rarefaction is a principal pathogenic factor in the development of severe organ dysfunction in CKD patients, especially CVD, cerebrovascular dysfunction, muscular atrophy, cachexia, and progression of kidney disease. Treatment strategies for microvascular disease are urgently needed.