Effects of skeletal unloading on the vasomotor properties of the rat femur principal nutrient artery

Spaceflight and prolonged bed rest induce deconditioning of the cardiovascular system and bone loss. Previous research has shown declines in femoral bone and marrow perfusion during unloading and with subsequent reloading in hindlimb-unloaded (HU) rats, an animal model of chronic disuse. We hypothesized that the attenuated bone and marrow perfusion may result from altered vasomotor properties of the bone resistance vasculature. Therefore, the purpose of this study was to determine the effects of unloading on the vasoconstrictor and vasodilator properties of the femoral principal nutrient artery (PNA), the main conduit for blood flow to the femur, in 2 wk HU and control (CON) rats. Vasoconstriction of the femoral PNA was assessed in vitro using norepinephrine, phenylephrine, clonidine, KCl, endothelin-1, arginine vasopressin, and myogenic responsiveness. Vasodilation through endothelium-dependent [acetylcholine, bradykinin, and flow-mediated dilation (FMD)] and endothelium-independent mechanisms [sodium nitroprusside (SNP) and adenosine] were also determined. Vasoconstrictor responsiveness of the PNA from HU rats was not enhanced through any of the mechanisms tested. Endothelium-dependent vasodilation to acetylcholine (CON, 86 ± 3%; HU, 48 ± 7% vasodilation) and FMD (CON, 61 ± 9%; HU, 11 ± 11% vasodilation) were attenuated in PNAs from HU rats, while responses to bradykinin were not different between groups. Endothelium-independent vasodilation to SNP and adenosine were not different between groups. These data indicate that unloading-induced decrements in bone and marrow perfusion and increases in vascular resistance are not the result of enhanced vasoconstrictor responsiveness of the bone resistance arteries but are associated with reductions in endothelium-dependent vasodilation

Thermal discomfort with cold extremities in relation to age, gender, and body mass index in a random sample of a Swiss urban population

<p>Abstract</p> <p>Background</p> <p>The aim of this epidemiological study was to investigate the relationship of thermal discomfort with cold extremities (TDCE) to age, gender, and body mass index (BMI) in a Swiss urban population.</p> <p>Methods</p> <p>In a random population sample of Basel city, 2,800 subjects aged 20-40 years were asked to complete a questionnaire evaluating the extent of cold extremities. Values of cold extremities were based on questionnaire-derived scores. The correlation of age, gender, and BMI to TDCE was analyzed using multiple regression analysis.</p> <p>Results</p> <p>A total of 1,001 women (72.3% response rate) and 809 men (60% response rate) returned a completed questionnaire. Statistical analyses revealed the following findings: Younger subjects suffered more intensely from cold extremities than the elderly, and women suffered more than men (particularly younger women). Slimmer subjects suffered significantly more often from cold extremities than subjects with higher BMIs.</p> <p>Conclusions</p> <p>Thermal discomfort with cold extremities (a relevant symptom of primary vascular dysregulation) occurs at highest intensity in younger, slimmer women and at lowest intensity in elderly, stouter men.</p

Aging and estrogen status: a possible endothelium-dependent vascular coupling mechanism in bone remodeling.

Bone loss with aging and menopause may be linked to vascular endothelial dysfunction. The purpose of the study was to determine whether putative modifications in endothelium-dependent vasodilation of the principal nutrient artery (PNA) of the femur are associated with changes in trabecular bone volume (BV/TV) with altered estrogen status in young (6 mon) and old (24 mon) female Fischer-344 rats. Animals were divided into 6 groups: 1) young intact, 2) old intact, 3) young ovariectomized (OVX), 4) old OVX, 5) young OVX plus estrogen replacement (OVX+E2), and 6) old OVX+E2. PNA endothelium-dependent vasodilation was assessed in vitro using acetylcholine. Trabecular bone volume of the distal femoral metaphysis was determined by microCT. In young rats, vasodilation was diminished by OVX and restored with estrogen replacement (intact, 82±7; OVX, 61±9; OVX+E2, 90±4%), which corresponded with similar modifications in BV/TV (intact, 28.7±1.6; OVX, 16.3±0.9; OVX+E2, 25.7±1.4%). In old animals, vasodilation was unaffected by OVX but enhanced with estrogen replacement (intact, 55±8; OVX, 59±7; OVX+E2, 92±4%). Likewise, modifications in BV/TV followed the same pattern (intact, 33.1±1.6; OVX, 34.4±3.7; OVX+E2, 42.4±2.1%). Furthermore, in old animals with low endogenous estrogen (i.e., intact and old OVX), vasodilation was correlated with BV/TV (R(2) = 0.630; P<0.001). These data demonstrate parallel effects of estrogen on vascular endothelial function and BV/TV, and provide for a possible coupling mechanism linking endothelium-dependent vasodilation to bone remodeling

Scattergrams showing the relation between plasma estrogen, uterine mass and endothelium-dependent vasodilation on trabecular bone volume (BV/TV) in the distal femur of young ovariectomized rats.

<p>A) plasma estrogen concentration from animals with estrogen levels within the detectable range; B) uterine mass, a biomarker for reproductive hormone concentration ovariectomized; and C) peak endothelium-dependent vasodilation of the femoral PNA. BV/TV was not related to either plasma estrogen (A) or uterine mass (B) in this group, whereas a significant (P<0.001) linear relation exists between BV/TV and percent PNA vasodilation (C).</p

The effects of ovariectomy and estrogen replacement on PNA endothelium-dependent vasodilation and trabecular bone volume in the femur of young rats.

<p>A) acetylcholine-induced vasodilation of the PNA, B) trabecular bone volume (BV/TV) of the distal femur, and C) the relation between peak endothelium-dependent vasodilation (%) and trabecular bone volume (%) in young intact, ovariectomized (OVX), and ovariectomized and estrogen replaced (OVX+E2) rats. A. Vasodilation was significantly lower in OVX rats, while estrogen replacement (OVX+E2) maintained vasodilator function to levels similar to that in intact animals. *Indicates the vasodilator response is significantly different between indicated groups (<i>P</i><0.05). B. Ovariectomy significantly reduced BV/TV vs. young intact rats, and OVX+E2 maintained trabecular bone volume (BV/TV) to levels equivalent to that of intact animals. *Indicates a significant difference from intact controls; ^†indicates a significant difference from OVX rats. C. Regression analysis indicates a linear relation between peak endothelium-dependent vasodilation (%) and trabecular bone volume (%) of the distal femur (<i>P</i><0.001). Values are means ± S.E; <i>n</i> = 9–11 animals per group.</p

Aging Reduces Skeletal Blood Flow, Endothelium-Dependent Vasodilation and Nitric Oxide Bioavailability in Rats

We determined whether aging diminishes bone blood flow and impairs endothelium‐dependent vasodilation. Femoral perfusion was lower in old animals, as well as endothelium‐dependent vasodilation and NO bioavailability. These effects could contribute to old age—related bone loss and the increased risk of fracture. Introduction: Aging has been shown to diminish bone blood flow in rats and humans. The purpose of this study was to determine whether blood flow to regions of the femur perfused primarily through the principal nutrient artery (PNA) are diminished with aging and whether this putative reduction in flow is associated with impaired endothelium‐dependent vasodilation. Materials and Methods: Blood flow was measured in conscious young adult (4–6 mo old) and aged (24–26 mo old) male Fischer‐344 rats using radiolabeled microspheres. Endothelium‐dependent vasodilation of the PNA was assessed in vitro using acetylcholine (ACh), whereas the contribution of the NO synthase (NOS) and cyclooxygenase (COX) signaling pathways to endothelium‐dependent vasodilation was determined using the NOS and COX inhibitors L‐NAME and indomethacin, respectively. Results: Femoral blood flow in the aged rats was 21% and 28% lower in the proximal and distal metaphyses, respectively, and 45% lower in the diaphyseal marrow. Endothelium‐dependent vasodilation was reduced with old age (young: 83 ± 6% maximal relaxation; aged: 62 ± 5% maximal relaxation), whereas endothelium‐independent vasodilation (sodium nitroprusside) was unaffected by age. The reduction in endothelium‐dependent vasodilation was mediated through impairment of the NOS signaling pathway, which resulted in lower NO bioavailability (young: 168 ± 56 nM; aged: 50 ± 7 nM). Conclusions: These data show that reductions in metaphyseal bone and diaphyseal marrow perfusion with old age are associated with diminished endothelium‐dependent vasodilation through an impairment of the NOS mechanism. Such age‐related changes in bone perfusion and vascular NO signaling could impact clinical bone loss, increase risk of fracture, and impair fracture healing in the elderly

Effects of age, ovariectomy (OVX), and ovariectomy and estrogen replaced (OVX+E2) on vasodilator responses of the PNA to increasing doses of the endothelium-independent, direct NO donor DEA NONOate in female rats.

<p>Responses were not different among groups. Values are means ± S.E; <i>n</i> = 9–11 animals per group.</p

The effects of ovariectomy and estrogen replacement on PNA endothelium-dependent vasodilation and trabecular bone volume in the femur of old rats.

<p>A) acetylcholine-induced vasodilation of the PNA, B) trabecular bone volume (BV/TV) of the distal femur, and C) the relation between peak endothelium-dependent vasodilation (%) and trabecular bone volume (%) in old intact, ovariectomized (OVX), and ovariectomized and estrogen replaced (OVX+E2) rats. A. Vasodilation was not different between old intact control and old OVX rats, while estrogen replacement (OVX+E2) elevated endothelium-dependent vasodilation to levels above that of intact and OVX animals. *Indicates the vasodilator response is significantly different between indicated groups (<i>P</i><0.05). B. Ovariectomy had no effect on BV/TV vs. old intact rats, whereas OVX+E2 elevated trabecular bone volume (BV/TV). *Indicates a significant difference from intact controls; ^†indicates a significant difference from OVX rats. C. Regression analysis indicates a linear relation between peak endothelium-dependent vasodilation (%) and trabecular bone volume (%) of the distal femur (<i>P</i><0.001). Values are means ± S.E; <i>n</i> = 9–11 animals per group.</p