Michiel P. de Boer

Rapid Decrease in Delivery of Chemotherapy to Tumors after Anti-VEGF Therapy: Implications for Scheduling of Anti-Angiogenic Drugs

Current strategies combining anti-angiogenic drugs with chemotherapy provide clinical benefit in cancer patients. It is assumed that anti-angiogenic drugs, such as bevacizumab, transiently normalize abnormal tumor vasculature and contribute to improved delivery of subsequent chemotherapy. To investigate this concept, a study was performed in non-small cell lung cancer (NSCLC) patients using positron emission tomography (PET) and radiolabeled docetaxel ([(11)C]docetaxel). In NSCLC, bevacizumab reduced both perfusion and net influx rate of [(11)C]docetaxel within 5 hr. These effects persisted after 4 days. The clinical relevance of these findings is notable, as there was no evidence for a substantial improvement in drug delivery to tumors. These findings highlight the importance of drug scheduling and advocate further studies to optimize scheduling of anti-angiogenic drugs.

Microvascular Dysfunction: A Potential Mechanism in the Pathogenesis of Obesity‐associated Insulin Resistance and Hypertension

Please cite this paper as: de Boer, Meijer, Wijnstok, Jonk, Houben, Stehouwer, Smulders, Eringa and Serné (2012). Microvascular Dysfunction: A Potential Mechanism in the Pathogenesis of Obesity‐associated Insulin Resistance and Hypertension. Microcirculation 19(1), 5–18.

Birth Weight Relates to Salt Sensitivity of Blood Pressure in Healthy Adults

The association between birth weight and blood pressure is well established but at present unexplained. According to the Borst-Guyton concept, chronic hypertension can occur only with a shift in the renal pressure–natriuresis relationship resulting in increased salt sensitivity of blood pressure. We assessed salt sensitivity of blood pressure in a group of 27 healthy adults whose birth weight was available. Birth weight was ascertained from birth certificates or announcements. Salt sensitivity of blood pressure was determined as difference in mean arterial pressure (MAP) between a 1-week high-salt (≈235 mmol NaCl/d) versus low-salt diet (≈55 mmol NaCl/d). Creatinine clearance was estimated according to the formula of Cockcroft and Gault. Birth weight was negatively associated with salt sensitivity of blood pressure (r=−0.60, P=0.002). The creatinine clearance was positively associated with birth weight (r=0.53; P=0.008) but did not influence the association between birth weight and salt sensitivity of blood pressure. Birth weight is associated with salt sensitivity of blood pressure, and this may play a role in the maintenance of elevated blood pressure in individuals with a low birth weight.

Insulin‐Induced Microvascular Recruitment in Skin and Muscle are Related and Both are Associated with Whole‐Body Glucose Uptake

Please cite this paper as: Meijer RI, de Boer MP, Groen MR, Eringa EC, Rattigan S, Barrett EJ, Smulders YM, Serne EH. Insulin‐induced microvascular recruitment in skin and muscle are related and both are associated with whole‐body glucose uptake. Microcirculation 19: 494–500, 2012.

Reduction in skin microvascular density and changes in vessel morphology in patients treated with sunitinib.

Hypertension is a common side effect in cancer patients treated with inhibitors of vascular endothelial growth factor/vascular endothelial growth factor receptor-2 signaling and may represent a marker of clinical benefit. Functional rarefaction (a decrease in perfused microvessels) or structural rarefaction (a reduction in anatomic capillary density) may play an important role in the development of hypertension. We investigated whether sunitinib caused impairment of microvascular function and/or reduction of capillary density in patients with metastatic renal cell cancer (mRCC). Sixteen mRCC patients were treated with sunitinib (50 mg/day). Assessments of 24-h ambulatory blood pressure, microvascular endothelial function by laser Doppler fluxmetry, and capillary density by capillary microscopy were performed at baseline and days 14 and 28. Median blood pressure had increased on day 14 (systolic 10 mmHg, P<0.01 and diastolic blood pressure 8 mmHg, P<0.01). Capillary density had decreased from 69 to 61 capillaries/mm2 (P<0.01). This decrease was related to the increase in systolic and diastolic blood pressure (r=−0.57, P<0.05 and r=−0.68, P<0.01, respectively). A more pronounced decrease in capillary density was associated with increased visibility of the subpapillary plexus (P=0.041). Preliminary findings indicated that median progression-free survival was significantly prolonged in patients with a greater than 6 capillaries/mm2 decrease in density as compared with patients with a less pronounced decrease (P=0.044). In conclusion, reduction in skin capillary density is associated with a rise in blood pressure during sunitinib therapy and, by itself, might be useful as a predictive marker of clinical outcome.

Insulin-Induced Changes in Microvascular Vasomotion and Capillary Recruitment are Associated in Humans

Insulin‐induced capillary recruitment is considered a significant regulator of overall insulin‐stimulated glucose uptake. Insulins action to recruit capillaries has been hypothesized to involve insulin‐induced changes in vasomotion. Data directly linking vasomotion to capillary perfusion, however, are presently lacking. We, therefore, investigated whether insulins actions on capillary recruitment and vasomotion were interrelated in a group of healthy individuals. We further assessed the role of capillary recruitment in the association between vasomotion and insulin‐mediated glucose uptake.

Globular adiponectin controls insulin-mediated vasoreactivity in muscle through AMPKα2

Decreased tissue perfusion increases the risk of developing insulin resistance and cardiovascular disease in obesity, and decreased levels of globular adiponectin (gAdn) have been proposed to contribute to this risk. We hypothesized that gAdn controls insulins vasoactive effects through AMP-activated protein kinase (AMPK), specifically its α2 subunit, and studied the mechanisms involved. In healthy volunteers, we found that decreased plasma gAdn levels in obese subjects associate with insulin resistance and reduced capillary perfusion during hyperinsulinemia. In cultured human microvascular endothelial cells (HMEC), gAdn increased AMPK activity. In isolated muscle resistance arteries gAdn uncovered insulin-induced vasodilation by selectively inhibiting insulin-induced activation of ERK1/2, and the AMPK inhibitor compound C as well as genetic deletion of AMPKα2 blunted insulin-induced vasodilation. In HMEC deletion of AMPKα2 abolished insulin-induced Ser(1177) phosphorylation of eNOS. In mice we confirmed that AMPKα2 deficiency decreases insulin sensitivity, and this was accompanied by decreased muscle microvascular blood volume during hyperinsulinemia in vivo. This impairment was accompanied by a decrease in arterial Ser(1177) phosphorylation of eNOS, which closely related to AMPK activity. In conclusion, globular adiponectin controls muscle perfusion during hyperinsulinemia through AMPKα2, which determines the balance between NO and ET-1 activity in muscle resistance arteries. Our findings provide a novel mechanism linking reduced gAdn-AMPK signaling to insulin resistance and impaired organ perfusion.

Body mass index is related to microvascular vasomotion, this is partly explained by adiponectin

obesity‐related microvascular dysfunction, including alterations in rhythmic changes in vascular diameter, so‐called ‘vasomotion’, may be important in the clustering of obesity with other cardiovascular risk factors. Adipokines have been suggested to play a role in obesity‐related vascular dysfunction. Alterations in vasomotion have been found using extreme body mass index (BMI) phenotypes. Whether these alterations can be translated to the general population is unknown. The aim was to retrospectively investigate relationships between BMI, vasomotion and adipokines in a population‐based cohort.

Phenotyping the Microcirculation With Contrast-Enhanced Ultrasound

In their interesting review, Struijker-Boudier et al1 provide a critical appraisal of current methods to study the microcirculation. In the extensive review, contrast-enhanced ultrasonography (CEU) remains undiscussed, whereas this method holds great promise as a tool in hypertension research. CEU is an imaging tool that enables quantification of microvascular perfusion in organs and tissues.2–5 It uses gas-filled microbubbles, typically with a lipid shell, that are inert, remain entirely within the vascular space, and possess an intravascular rheology similar to that of erythrocytes.2 Therefore, they specifically enhance imaging of the (micro-)vessels. During intravenous infusion of …

PS9 - 14. Perivascular adipose tissue characteristics are related with in vivo microvascular and metabolic insulin sensitivity

The rising prevalence of obesity and overweight leads to an increase in obesity-associated disorders, most prominently type 2 diabetes and cardiovascular disease. These conditions are linked by microvascular insulin resistance. Perivascular adipose tissue (PVAT) has been hypothesized to determine microvascular responses to insulin through the secretion of adipokines, thereby regulating metabolic insulin sensitivity.