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. Author manuscript; available in PMC: 2023 May 1.
Published in final edited form as: Exp Physiol. 2022 Apr 12;107(5):450–461. doi: 10.1113/EP090168

Young, Non-Hispanic Black Men and Women Exhibit Divergent Peripheral and Cerebral Vascular Reactivity

John D Akins 1, Zachary T Martin 1, Jordan C Patik 1,2, Bryon M Curtis 1,3, Jeremiah C Campbell 1, Guillermo Olvera 1,3, R Matthew Brothers 1
PMCID: PMC9058228  NIHMSID: NIHMS1793209  PMID: 35344241

Abstract

In the U.S., cardiovascular and cerebrovascular diseases remain more prominent in the non-Hispanic Black (BL) population relative to other racial/ethnic groups. Typically, sex differences emerge in the manifestation of these diseases, though these differences may not fully materialize in the BL population. While numerous mechanisms are implicated, differences in vascular function likely contribute. Research has demonstrated blunted vasodilation in several vascular regions in BL versus non-Hispanic White individuals, though much of this work did not assess sex differences. Therefore, this study aimed to ascertain if indices of vascular function are different between young, BL women (BW) and men (BM). Eleven BW and 15 BM (22 (4) vs. 23 (3) y) participated in this study. Each participant underwent testing for brachial artery flow-mediated dilation (FMD), post-occlusive reactive hyperemia (RH), and cerebral vasomotor reactivity during rebreathing-induced hypercapnia. BW exhibited greater adjusted FMD than BM (P < 0.05 for all), but similar or lower RH when assessed as blood velocity (P > 0.39 for all) or blood flow reactivity (P < 0.05 for all), respectively. Across a range of hypercapnia, BW had greater middle cerebral artery blood velocity and cerebrovascular conductance index than BM (P < 0.001 for both). These preliminary data suggest that young, BW have greater vascular function relative to young, BM, though this was inconsistent across different indices. These findings provide insight into the divergent epidemiological findings between BM and BW. Further research is needed to elucidate possible mechanisms and relate these physiological responses to epidemiological observations.

Keywords: cardiovascular disease, cerebrovascular disease, non-Hispanic Black, vascular function

Introduction

All-cause cardiovascular disease (CVD) prevalence and mortality remain prominent issues in the United States (Virani et al., 2021) despite continued medical advancements and interventions. Indeed, after a brief downward trend starting in the 1990s, adult CVD prevalence increased from 35% to nearly 50% over the past 5–10 y (Mozaffarian et al., 2016; Virani et al., 2021). Both men (~36% to ~54%) and women (~33% to ~44%) experienced this rise in disease prevalence, which ultimately manifests as an additional 70,000 CVD-related deaths per year (Mozaffarian et al., 2016; Virani et al., 2021).

While CVD prevalence and mortality continue an upward trajectory, not all population groups are affected equally. For instance, non-Hispanic Black (BL) individuals exhibit the highest prevalence of CVD and hypertension and one of the highest CVD mortality rates compared to other populations (Virani et al., 2021). Additionally, BL individuals develop prehypertension and hypertension at a much younger age (Kit et al., 2015) and experience greater morbidity and mortality from hypertension (Maraboto & Ferdinand, 2020). These observations extend to cerebrovascular diseases and mortality, as the BL population has a greater cerebrovascular disease incidence, prevalence, and age-adjusted mortality than other racial/ethnic groups (Virani et al., 2021). Later in life, BL individuals also suffer from greater cognitive impairment (Chen et al., 2021) and a higher prevalence of Alzheimer’s disease and related dementias (Matthews et al., 2019), relative to other racial/ethnic groups. Interestingly, sex differences emerge such that BL women (BW) have distinct responses depending on the epidemiological category. For instance, while women of other racial/ethnic groups have a lower prevalence of all-cause CVD relative to their respective male counterparts, BW suffer from a nearly identical CVD prevalence as BL men (BM) (Virani et al., 2021). Contrarily, BW experience reduced age-adjusted mortality from stroke compared to BM, which is not seen in other groups (Virani et al., 2021). Accordingly, the CVD disparities between BM and BW seem to be unique and remain incompletely understood.

CVD and cerebrovascular disease genesis remain inherently multifactorial processes. Differences in macro- and microvascular function, however, prevail as invariable hallmarks of various CVD and cerebrovascular disease. Reduced vascular function often precipitates the development of conditions such as atherosclerosis and coronary disease (Vanhoutte et al., 2017). Accordingly, these reductions may catalyze the development of overt disease. In this regard, the BL population exhibits blunted vasodilation (Perregaux et al., 2000; Stein et al., 2000; Campia et al., 2002; Hurr et al., 2015; Patik et al., 2018) and exaggerated vasoconstriction (Calhoun et al., 1993; Stein et al., 2000; Ray & Monahan, 2002; Vranish et al., 2018) at rest and to varying stimuli compared to matched non-Hispanic, White (WH) individuals. Mechanistically, the blunted vasodilation in BL individuals often derives from reduced nitric oxide (NO) bioavailability (Kalinowski et al., 2004; Patik et al., 2018). Exaggerated vasoconstriction or augmented vascular tone, on the other hand, may stem from several sources, as detailed by Brothers et al. in a recent review (2020), and may ultimately hinder vasodilation.

The extent of differences in the control of vascular tone often changes responsiveness to different physiological maneuvers used to assess vascular function. In this regard, brachial artery flow-mediated dilation (FMD; an index of macrovascular function) is blunted in BL versus WH men and women following a period of brief cuff occlusion (Perregaux et al., 2000; Campia et al., 2002), although these results are equivocal (Gokce et al., 2001). Further, cerebrovascular responsiveness to rebreathing-induced hypercapnia is reduced in BL versus WH participants (Hurr et al., 2015). In these studies, however, comprehensive measures of reactive hyperemia (RH), an index of microvascular function (Perregaux et al., 2000; Campia et al., 2002), or direct sex comparisons (Perregaux et al., 2000; Gokce et al., 2001; Campia et al., 2002; Hurr et al., 2015) were not elucidated. Furthermore, in those studies assessing FMD, many of them did not use modern technology (e.g., duplex Doppler ultrasound, continuous wall tracking) or recommendations for assessing FMD. Therefore, the purpose of this study was to better understand peripheral vasodilatory responses and cerebral vasomotor reactivity in young, BM and BW. We hypothesized that BM and BW would exhibit divergent 1) FMD and RH responses to a period of brief cuff occlusion and 2) cerebral vasomotor reactivity to rebreathing-induced hypercapnia.

Methods

Ethical Approval:

The Institutional Review Board at the University of Texas at Arlington approved all procedures for this study (UTA IRB #2016–0847, #2017–0856, and #2019–0318). Participants were given a verbal description of all procedures, purposes, and risks involved before providing their informed, written consent. This study conformed to the standards set by the Declaration of Helsinki (apart from registration in a database).

Participant Characteristics:

Eleven young, BW and 15 young, BM participated in this study. Subject characteristics are presented in Table 1. To determine eligibility, each participant self-reported their racial identity. Tobacco users and competitive athletes were excluded. Additionally, all participants were free from overt cardiovascular, metabolic, and neurological disease and were not taking vasoactive prescription medications or supplements. Participants fasted a minimum of 4-h, abstained from caffeine a minimum of 12-h, and abstained from alcohol and strenuous activity for 24-h before each experimental visit. Women were studied in the low hormone phase of their menstrual cycles as assessed by venous blood sample analysis (LabCorp; Dallas, TX; Table 1). Following arrival to the lab, measures of height and mass were collected using a digital scale and stadiometer (Seca 769, Seca North America; Chino, CA). Then, each participant laid supine on a patient bed for instrumentation, measures of baseline cardiovascular parameters, and the assessment of peripheral and cerebral vascular function.

Table 1:

Subject characteristics for the Black men (n = 15) and women (n = 11).

Black Men Black Women
Age (y) 23 (3) 22 (4)
Height (cm) 177.7 (6.0) 160.6 (5.0)
Mass (kg) 74.9 (11.3) 61.0 (9.0)
BMI (kg • m−2) 23.7 (3.2) 23.8 (4.2)
SBP (mmHg) 119 (8) 120 (8)
DBP (mmHg) 71 (6) 73 (8)
Serum Estradiol (pg • mL−1) - 39.1 (12.9)
Serum Progesterone (ng • mL−1) - 0.5 (0.4)
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BMI: Body Mass Index; SBP: Systolic Blood Pressure; DBP: Diastolic Blood Pressure. Data are presented as mean (SD).

Instrumentation:

Each participant was instrumented for the continuous measurement of heart rate, via electrocardiography (CardioCard, Nasiff Associates; Central Square, NY), and intermittent blood pressure, via electrosphygmomanometry (Tango+, SunTech; Raleigh, NC). On the arm contralateral to the intermittent blood pressure cuff, non-invasive, beat-to-beat mean arterial blood pressure was measured via finger photoplethysmography during the rebreathing protocol (MAP; Finometer Pro, Finapres Medical Systems; Netherlands).

Peripheral vascular function was assessed using FMD and RH, as previously described (Thijssen et al., 2019). Briefly, a pneumatic cuff connected to a rapid inflation device (Hokanson Model E20 Rapid Cuff Inflator; Bellvue, WA) was placed just distal to the antecubital fossa and the brachial artery was imaged using high-resolution, duplex Doppler ultrasound. An adjustable frequency (10–13 MHz) linear array transducer (LOGIQ P5, GE Healthcare; Chicago, IL) was selected for optimal B-mode signals of the brachial artery and held in a stereotactic clamp 5–10 cm proximal to the antecubital fossa. Once a suitable image was obtained and optimized for clear delineation between the lumen and vessel walls, duplex mode (at a pulsed frequency of 5 MHz) was utilized for the continuous measurement of brachial artery diameter and blood velocity. The sample volume was set to encompass the entire lumen, without extending into the surrounding tissue, at an insonation angle of 60°. All images were recorded using a commercially available screen capture software (Elgato Video Capture, Corsair; Fremont, CA). Each image was analyzed offline using continuous edge-detection software (Cardiovascular Suite, Quipu; Pisa, ITA) along a section of the artery with clearly defined vessel walls, while second-by-second blood velocity was taken as the entire Doppler envelope.

Cerebral blood flow was indexed as middle cerebral artery (MCA) mean velocity (VMCA) using transcranial Doppler ultrasound (TCD) following standard procedures (Willie et al., 2011). Briefly, a 2-MHz TCD probe (Neurovision TC, Multigon Industries Inc.; Yonkers, NY) was placed on the left temple, superior to the zygomatic arch, and attached using an adjustable headband to maintain probe placement. Following insonation of the MCA through the transtemporal window, the TCD signal was optimized by adjusting the probe angle and insonation depth, gain, and amplitude. Each participant was then fitted with a mouthpiece attached to a three-way stopcock (Hans Rudolph; Shawnee, KS) that permitted rapid switching between ambient air and a 5-L rubber rebreathing bag (GPC Medical Ltd.; New Delhi, India) pre-filled with the participant’s expired air. Partial end-tidal CO2 pressure (PETCO2), a surrogate for the partial pressure of arterial CO2, was measured continuously through a sampling line connecting the mouthpiece to a capnograph (Capnocheck Plus, Smiths Medical; Dublin, OH). Peripheral oxygen saturation (SpO2) was monitored throughout the protocol with a digital pulse oximeter (Capnocheck Plus, Smiths Medical; Dublin, OH) placed on a finger. Respiratory excursions were measured with a piezo-electric respiration transducer (Pneumotrace II, UFI; Morro Bay, CA) placed around the abdomen.

Protocol:

Following instrumentation and a 15 min stabilization period, FMD and RH were assessed. After a 2 min baseline, during which brachial artery diameter and blood velocity were continuously measured, the pneumatic cuff was inflated to ~220 mmHg for 5 min to elicit ischemia. Upon cuff deflation, brachial artery diameter and blood velocity were recorded for an additional 3 min.

Immediately after the FMD/RH assessment, each participant was instrumented as outlined above for the hypercapnic challenge. Each participant breathed ambient air for 3 min for baseline data collection of VMCA, MAP, PETCO2, SpO2, heart rate, and respiratory rate. Immediately after this baseline period, each participant performed the rebreathing protocol as previously described (Hurr et al., 2015). Briefly, the three-way stopcock Y-valve was switched from ambient air to the rebreathing bag such that the participant expired into and inspired from the 5-L bag, slowly raising PETCO2. Rebreathing was continued until the participant reached discomfort, a discernable plateau in PETCO2 was established, or 3-min elapsed, whichever came first. Following rebreathing, the Y-valve was switched back to ambient air for a 3-min recovery period. Throughout the rebreathe protocol, 100% oxygen was continuously administered into the 5-L bag to maintain arterial normoxia (SpO2 ~97%) (Hurr et al., 2015).

Data Acquisition and Analysis:

Brachial artery responses following a brief period of forearm ischemia were continuously measured on a second-by-second basis. Brachial artery diameter (D; cm) and mean blood velocity (VBA; mean of summed anterograde and retrograde velocities; cm • s−1) were used to subsequently calculate shear rate (4 • VBA • D−1; s−1) and blood flow (π • [D • 0.5]2 • VBA • 60; mL • min−1). Peak VBA, shear rate, and blood flow were identified as the highest three-second rolling average values. VBA and shear area-under-the-curve (AUC) were calculated as the sum of second-by-second blood velocity and shear rate, respectively, from the end of occlusion until peak brachial artery diameter (Thijssen et al., 2019). Both total (Flow AUCT) and incremental (i.e., above baseline; Flow AUCI) blood flow AUC were calculated using second-by-second flow data from end occlusion to peak dilation. The latter was calculated to account for possible differences in baseline blood flow between groups.

All data during the hypercapnic challenge were collected using a data acquisition system and software (PowerLab and LabChart 8, ADInstruments; Colorado Springs, CO) and stored on a laboratory computer for offline analysis. All variables were taken as a 1 min average during baseline and on a breath-by-breath basis during the rebreathing protocol. Cerebrovascular conductance index (CVCi) was calculated as VMCA • MAP−1 and expressed in both absolute and relative (i.e., percent change from baseline; ΔCVCi) terms. The absolute change in PETCO2 (ΔPETCO2) was assessed over the entire rebreathe and MAP and CVCi were recorded as three breath averages at predetermined stages (i.e., ΔPETCO2 of 3, 6, 9, and 12 mmHg). The linear slope of each individual’s absolute and relative response was calculated and averaged to determine mean cerebral vasomotor reactivity (CVR) during hypercapnic rebreathing.

Statistical Analysis:

Comparisons for FMD and RH were completed using unpaired, two-tailed, Welch’s t-tests. Allometrically scaled FMD was analyzed as previously described (Atkinson & Batterham, 2013), while shear-corrected FMD was analyzed using ANCOVA, whereby shear AUC served as the covariate. Hemodynamic responses at baseline and during the rebreathe were analyzed via mixed-effects models with the factors of ΔPETCO2 stage (baseline, Δ3 mmHg, Δ6 mmHg, Δ9 mmHg, and Δ12 mmHg) and sex (BM and BW). The mixed-effects models were run using a compound symmetry covariance matrix and fit using restricted maximum likelihood. Additionally, only 8 of the 11 BW were able to complete the Δ12 mmHg hypercapnic stage. In the case of significant interactions, post-hoc Holm-Sidak corrections were performed. Unpaired, two-tailed, Welch’s t-tests were performed for the slopes of the PETCO2 versus CVCi (absolute and relative) relation. All data were analyzed using GraphPad Prism 9 (GraphPad Software Inc., La Jolla, CA) and SPSS 28 (IBM Corp.; Armonk, NY) and presented as mean (SD). The level of statistical significance was set a priori at α = 0.05.

RESULTS

Flow-Mediated Dilation and Reactive Hyperemia

At baseline, BW had a smaller brachial artery diameter than BM (P = 0.002; Table 2). Given the differences in baseline diameter between the BW and BM, we compared the %FMD response, adjusted for baseline diameter, using allometric scaling as previously described (Atkinson & Batterham, 2013). Following allometric scaling, the %FMD response was greater in the BW compared to the BM (9.00 (3.19) vs. 5.95 (3.09)%; P = 0.044; Figure 1A), aligning with the findings of the conventional %FMD (9.27 (3.28) vs. 5.84 (2.78)%; P = 0.011; Figure 1B). To account for the influence of shear rate, the primary stimulus for vasodilation, allometrically scaled %FMD was also analyzed using shear AUC as a covariate. Accordingly, shear-adjusted %FMD remained significantly greater in the BW versus BM (9.22 (2.83) vs. 5.79 (2.07)%; P = 0.024).

Table 2:

Additional brachial artery flow-mediated dilation (FMD) and hemodynamic parameters following a brief period of forearm ischemia.

Black Men Black Women P-value
Dbase (mm) 3.69 (0.65) 2.97 (0.38) 0.002
Absolute ΔD (mm) 0.21 (0.12) 0.27 (0.09) 0.165
Shear Corrected FMD (%) 5.79 (2.48) 9.33 (2.62) 0.005
Time to Peak D (s) 58.6 (23.7) 47.0 (14.0) 0.139
VBA Peak (cm • s−1) 79.4 (19.6) 77.0 (20.0) 0.766
VBA AUC (cm) 47.5 (15.8) 42.5 (12.7) 0.381
Peak Shear (s−1) 917.4 (315.4) 1040.1 (208.4) 0.245
Shear AUC (AU) 30,276 (13,368) 28,988 (7,120) 0.754
Baseline Flow (mL • min−1) 84.3 (67.6) 52.7 (43.3) 0.160
Peak Flow (mL • min−1) 495.4 (196.9) 342.1 (170.4) 0.045
ΔFlow (%baseline-peak) 865.9 (764.4) 654.4 (211.2) 0.322
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Shear corrected FMD represents the non-allometrically scaled FMD covaried for Shear Area-Under-the-Curve (AUC) to peak diameter. Time to peak values are measured as time post forearm cuff occlusion. Black Men: n = 15; Black Women: n = 11. D: Diameter; FMD: Flow-Mediated Dilation, non-allometrically scaled; VBA: Brachial Artery Blood Velocity; AU: Arbitrary Units. Data are presented as mean (SD) and compared using two-tailed, unpaired, Welch’s t-tests.

Figure 1:

Figure 1:

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Allometrically scaled brachial artery flow-mediated dilation (FMD; A), shear area-under-the-curve (AUC; B), incremental flow AUC (C), and total flow AUC (D) responses to a brief period of forearm ischemia. Shear AUC and flow AUC are summed from end-occlusion to peak brachial artery dilation. Data are from 11 BW and 15 BM. Panel A was analyzed using an analysis of covariance, while Panels B-D were analyzed using two-tailed, unpaired, Welch’s t-tests. (*): P < 0.05

Following cuff occlusion, neither peak VBA (P = 0.778; Table 2) nor VBA AUC (P = 0.387; Table 2) were different between the BW and BM. Additionally, peak shear (P = 0.245; Table 2) and shear AUC (P = 0.754; Table 2) were similar between BW and BM. Peak blood flow, however, was different between BW and BM (P = 0.046; Table 2). This difference was abolished after normalizing peak to baseline blood flow in BW and BM (P = 0.322; Table 2). Compared to BM, BW had a reduced FlowAUCI (133.6 (61.1) vs. 220.3 (130.7) mL, respectively; P = 0.035; Figure 1C) and FlowAUCT (175.0 (90.2) vs. 303.4 (206.9) mL, respectively; P = 0.046; Figure 1D).

Rebreathing-Induced Hypercapnia

The MAP response to rebreathing-induced hypercapnia (Table 3) was similar between the BW and BM at baseline and during all stages of hypercapnia (Group P = 0.415; Interaction P = 0.114). Further, respiratory rate and SpO2 were similar between groups during hypercapnia (P > 0.519 for both; Table 3). At baseline, the BW had a greater VMCA than the BM, which extended to each degree of hypercapnia (all P < 0.001; Table 2).

Table 3:

Respiratory and cardiovascular parameters at baseline and during the hypercapnic challenge.

Hypercapnia Stage (ΔPETCO2)
 P – values
Baseline Δ3 mmHg Δ6 mmHg Δ9 mmHg Δ12 mmHg Group PETCO2 Interaction
Respiratory Rate (breaths • min −1 )
 Black Men 15 (4) 13 (5) 13 (5) 13 (5) 14 (5) 0.519 0.018 0.071
 Black Women 12 (4) 11 (2) 12 (3) 13 (3) 15 (4)
SpO2 (%)
 Black Men 97 (1) 97 (1) 98 (1) 98 (1) 98 (1) 0.842 0.010 0.212
 Black Women 97 (1) 96 (3) 98 (2) 98 (1) 98 (1)
MAP (mmHg)
 Black Men 89 (7) 88 (9) 89 (8) 90 (9) 91 (9) 0.415 <0.001 0.114
 Black Women 91 (9) 88 (11) 93 (8) 94 (8) 95 (10)
VMCA (cm • s−1)
 Black Men 59.5 (9.4) 59.3 (11.2) 62.9 (11.4) 70.0 (12.4) 72.5 (14.7) <0.001 <0.001 <0.001
 Black Women 72.8 (11.3)* 80.0 (14.7)* 91.6 (14.7)* 98.1 (15.8)* 105.8 (18.2)*
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Black Men: n = 15; Black Women: n = 11, except for Δ12 mmHg, where n = 8. SpO2: Peripheral Oxygen Saturation; MAP: Mean Arterial Blood Pressure; VMCA: Middle Cerebral Artery Blood Velocity; PETCO2: Partial End-Tidal Carbon Dioxide Pressure.

(*):

P < 0.05 vs. black men at the same ΔPETCO2 stage. Data are presented as mean (SD) and compared using mixed-effects models.

Given the lack of difference in MAP, the difference in VMCA manifested in our measures of cerebral vascular tone as BW exhibited an augmented absolute CVCi at baseline relative to the BM (0.80 (0.10) vs. 0.68 (0.13) cm • s−1 • mmHg−1; P = 0.038; Figure 2A). This pattern was also observed at each ΔPETCO2 stage (Δ3: 0.91 (0.11) vs. 0.67 (0.13) cm • s−1 • mmHg−1; Δ6: 0.98 (0.10) vs. 0.71 (0.12) cm • s−1 • mmHg−1; Δ9: 1.04 (0.09) vs. 0.78 (0.13) cm • s−1 • mmHg−1; Δ12: 1.11 (0.11) vs. 0.80 (0.16) cm • s−1 • mmHg−1; all P < 0.001; Figure 2A). These absolute CVCi differences also manifested in the slope of the PETCO2 and CVCi relation (i.e., cerebrovascular reactivity; CVR), whereby BW had a greater slope than BM (0.024 (0.010) vs. 0.012 (0.006) cm • s−1 • mmHgMAP−1 • mmHgPETCO2−1; P = 0.004; Figure 2B)

Figure 2:

Figure 2:

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Absolute cerebral vascular conductance index (CVCi; A) and the slope of the partial end-tidal CO2 tension (PETCO2) and CVCi relation (i.e., cerebrovascular reactivity; CVR; B) at baseline and during rebreathing-induced hypercapnia. BW are represented by squares and BM are represented by circles. Data are from 11 BW and 15 BM, except for a PETCO2 of Δ12 mmHg, whereby only 8 BW reached this stage of hypercapnia. CVR is measured as the change in blood velocity per unit change in blood pressure, per unit change in PETCO2. Data were analyzed using a mixed-effects model (panel A) and a two-tailed, unpaired, Welch’s t-test (panel B). (*): P < 0.05 between BW and BM at each PETCO2 stage for panel A and between the slopes in panel B.

While baseline absolute CVCi differences existed between the BW and BM, they did not affect the relative CVCi response. At each stage of ΔPETCO2, the BW exhibited an augmented ΔCVCi relative to the BM (Δ3: 12.9 (5.3) vs. 0.1 (9.4)%; Δ6: 23.0 (6.8) vs. 5.5 (10.2)%; Δ9: 29.9 (12.9) vs. 16.0 (11.2)%; Δ12: 40.7 (16.8) vs. 19.0 (12.3)%; all P < 0.05; Figure 3A). Further, these baseline differences did not affect CVR, such that BW maintained a greater slope than BM (3.07 (1.50) vs. 1.77 (0.94) %Δ • mmHg−1; P = 0.022; Figure 3B).

Figure 3:

Figure 3:

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Relative cerebral vascular conductance index (ΔCVCi; A) and the slope of the partial end-tidal CO2 tension (PETCO2) and ΔCVCi relation (i.e., cerebrovascular reactivity; CVR; B) at baseline and during rebreathing-induced hypercapnia. BW are represented by squares and BM are represented by circles. Data are from 11 BW and 15 BM, except for a PETCO2 of Δ12 mmHg, whereby only 8 BW reached this stage of hypercapnia. Data were analyzed using a mixed-effects model (panel A) and a two-tailed, unpaired, Welch’s t-test (panel B). (*): P < 0.05 between BW and BM at each PETCO2 stage for panel A and between the slopes in panel B.

DISCUSSION

This study aimed to determine whether young, BM and BW exhibit disparate vascular function. Accordingly, we tested brachial artery FMD and RH following a brief period of forearm ischemia for peripheral conduit and resistance artery function, respectively, while changes in VMCA and CVCi during hypercapnia represented cerebral vascular function. The primary findings were that young, BW had 1) greater FMD, 2) similar RH following cuff occlusion, and 3) greater VMCA and CVCi responses to a hypercapnic challenge relative to young, BM. Accordingly, these preliminary data suggest that young, BW exhibit greater peripheral conduit artery function, similar peripheral resistance vessel function, and greater cerebral blood vessel function relative to young, BM.

Flow-Mediated Dilation

The finding of a greater FMD in the young, BW departs from previous literature including race-by-sex differences in brachial artery reactivity (Perregaux et al., 2000; Campia et al., 2002; Dass et al., 2017). Indeed, these studies noted almost no difference between BM and BW. Several explanations may contribute to the different results in these previous studies. The participants in these studies 1) had a larger Dbase (e.g., at least 0.4 mm greater than the current study), 2) had variable absolute diameter changes (e.g., men were not different, but women had smaller absolute dilation than the present study), 3) were older (>7 y), and 4) had a greater BMI (>3 kg • m−2). Noting these differences, we can at least partially determine the interplay of Dbase and shear rate on FMD. Despite allometrically scaling %FMD for Dbase (Atkinson & Batterham, 2013) or covarying %FMD for the shear stimulus (Pyke & Tschakovsky, 2007; Thijssen et al., 2019), %FMD, and thus conduit artery endothelial function, remained greater in the young, BW relative to the young, BM in this study. Based on the findings in middle-aged and overweight/obese individuals, however, this function may not be immune to the typical effects of aging (Celermajer et al., 1994; Nishiyama et al., 2008a) or increases in BMI (Hashimoto et al., 1998; Arkin et al., 2008), which may explain some of the discrepancies between the current study and previous studies (Perregaux et al., 2000; Campia et al., 2002; Dass et al., 2017). Further, the greater function in young, BW may be lost at an earlier age given the augmented prevalence of CVD in BW (Virani et al., 2021).

With the present data, an interesting intersection of the current race-by-sex difference in FMD and epidemiological data now emerges. While FMD can be used as a tool for the non-invasive determination of vascular health and prediction of CVD progression (Celermajer et al., 1992; Thijssen et al., 2019), the greater FMD in the BW in this study does not parallel the development of CVD in this population. Perhaps this discrepancy stems from the age of the participants in the present study (e.g., ~23 y) and the onset age of overt CVD (e.g., midlife). As FMD declines with age (Celermajer et al., 1994), the greater FMD in these young, BW versus BM and equivalent epidemiological CVD prevalence between groups may indicate an accelerated vascular aging phenotype in BW.

Reactive Hyperemia

Interestingly, despite our findings for %FMD, the RH response was variable, depending on the measurement. Peak flow, flow AUCT, and flow AUCI were all greater in the BM, although the difference in peak flow was abolished after normalizing to baseline flow. Furthermore, neither VBA measure was different between groups. Previous data from Morris et al. (2013) using pulse amplitude tonometry (PAT) would suggest the opposite of our reactive hyperemia findings. However, the population studied was ~25 y older than the BW and BM in this study, which may obfuscate comparisons with the present data as microvascular function degrades with age, particularly in the presence of CVD risk factors (Rosenberry et al., 2018; Horiuchi & Okita, 2020). Perhaps another reason for these disparate RH findings is the method by which RH was assessed. While PAT measures augmentations in finger pressure and typically correlates well with Doppler ultrasound in health and disease (Lee et al., 2012). the simultaneous measurement of blood velocity and arterial diameter with Doppler ultrasound may be better suited to detect group differences.

Simple calculations of brachial artery blood flow involve both VBA and D (e.g., D2 • 4−1). In this regard, blood flow can be modified by either variable, either individually or in combination. Immediately following cuff occlusion, the rapid surge in blood flow is primarily driven by a large augmentation of VBA, rather than changes in D. In the current study, peak and AUC VBA were similar between the BW and BM. Accordingly, the gradient for blood flow may not have differed between the BW and BM. While peak and AUC VBA are common measures of RH (Rosenberry & Nelson, 2020) that relate well to CVD event-free survival (Anderson et al., 2011), they do not fully account for the differences in blood flow. Indeed, in the present study, the primary influence for the flow differences between the BW and BM is the sizable difference in D (~0.7 mm). While our observed difference in D provides a mathematical reason, it does not explain why.

As the increase in blood flow corrects for the ischemic stimulus (Rosenberry et al., 2018; Rosenberry et al., 2019; Rosenberry & Nelson, 2020), it is reasonable that the greater the stimulus, the greater the RH. Indeed, previous data suggest that after correcting for tissue desaturation (i.e., ischemia), differences in RH are abrogated (Rosenberry et al., 2019). In the present study, while BMI was similar, the BM weighed nearly 14 kg more than the BW. While direct measures of adiposity or forearm tissue mass were not made, it is highly likely that the BM in this study had a greater amount of lean forearm tissue. Indeed, previously reported sex differences for post-occlusive RH were ameliorated after normalizing for muscle mass (Nishiyama et al., 2008b). Therefore, the observed sex difference in RH as determined by blood flow may be directly related to the greater amount of ischemic tissue rather than an inherent disparity in peripheral microvascular function. This may be further illustrated by the observation that the percent change in blood flow from baseline to peak was not different between the BM and BW. However, FlowAUCI remained different between the two groups, therefore warranting caution in the interpretations of RH in the present study.

Cerebrovascular Responses to Rebreathing-Induced Hypercapnia

The present data extend previous findings from our group (Hurr et al., 2015) demonstrating reduced CVR in young, BL individuals by establishing sex differences within this group. Previous work by Favre et al. (2020) and Tallon et al. (2020) included measures of cerebral vasomotor tone (e.g., cerebral vascular resistance) during hypercapnia in young men and women. While not the primary outcome of these studies, neither group noted differences in the change in vascular resistance across a change in PETCO2 of ~6–10 mmHg while the participants were supine (Favre et al., 2020; Tallon et al., 2020). These differences accounted for an absolute reduction in resistance of ~0.12–0.19 mmHg・cm−1・s−1 at Δ6 mmHg PETCO2 (Favre et al., 2020) and ~0.41–0.48 mmHg・cm−1・s−1 at Δ10 mmHg PETCO2 (Tallon et al., 2020), which equate to reductions in vascular resistance of ~13–17% and ~32–40%, respectively. By comparison, the BW in the present study would fall at the low end of these ranges for similar PETCO2 values, while the BM barely achieve half of this indexed vasodilation. Interestingly, despite our apparent differences in cerebral vasomotor tone with these previous studies, our observed differences for baseline and hypercapnic VMCA were also noted by Tallon et al. (2020). These findings are corroborated by a recent cross-sectional examination highlighting similar differences in resting VMCA between men and women (Alwatban et al., 2021). None of these studies, however, reported the racial/ethnic composition of their participants. In the event of a mixed cohort, racial/ethnic differences in cerebral vascular reactivity may not be readily apparent. Accordingly, the additional sex difference in cerebral vasodilation may be a characteristic unique to young, BL individuals.

Ultimately, any reduction in cerebral blood flow is detrimental to cerebral health, particularly when the effects are cumulative from early life. The observed reductions in CVR in young, BL individuals (Hurr et al., 2015) may explain the greater risk for stroke (Virani et al., 2021), cognitive impairment (Potter et al., 2009; Chen et al., 2021), and Alzheimer’s disease and related dementias (Matthews et al., 2019) in the BL population. When accounting for metrics such as age-adjusted stroke mortality, further differences emerge such that BW are seemingly protected relative to BM (Virani et al., 2021), which may be a result of the greater CVR in young, BW. These early life differences in CVR may provide some degree of cerebrovascular protection that delays stroke-related mortality to later life. More research, however, is needed to understand the mechanisms leading to altered cerebral blood flow and the disparate cerebrovascular disease risk in this unique race-by-sex manner.

Possible Contributing Mechanisms

As each of these vasoreactivity tests elicit dilation to varying degrees, it is important to understand their underlying mechanisms and how they relate back to the BL population. Previous literature demonstrates blunted NO bioavailability in BL individuals (Kalinowski et al., 2004; Patik et al., 2018), manifesting as blunted vasodilation. In this regard, NO has been implicated in the FMD responses in different populations. For instance, distal forearm occlusion, such as the protocol in the present study, has been demonstrated to elicit FMD that is ~60–70% NO-mediated (Green et al., 2014). Ultimately the differences in FMD between the BM and BW may be the byproduct of altered NO status. The alteration in NO bioavailability may occur secondary to altered redox status (Kalinowski et al., 2004; Patik et al., 2018), but may also be influenced by the properties of the blood. Previous research notes that hemoglobin concentrations (Pan & Habicht, 1991) and hematocrit (De Simone et al., 1990) are lower in women versus men, which persists in Black individuals. Greater hemoglobin concentrations in the BM may lead to augmented NO scavenging, which would ultimately reduce vascular function, though the influence of hemoglobin primarily derives from cell-free hemoglobin (Gladwin et al., 2004). Whether cell-free hemoglobin concentrations are different between BM and BW appears to be unknown. Beyond hemoglobin, increased hematocrit leads to more viscous blood in BM versus BW (De Simone et al., 1990), which should increase vascular shear stress in the BM. Accordingly, the shear rate in the present study may be underestimating the difference in vascular shear stress between the groups. However, if the BM in the current study did have greater blood viscosity, their shear corrected FMD would ultimately be reduced, exacerbating the differences in FMD between the BM and BW. Further research is needed to better understand the interaction between redox status, blood rheological properties, NO bioavailability, and FMD in BM and BW.

Unlike FMD, the constitutive role of NO during post-occlusive RH is uncertain. While some studies have found small to large contributions of NO during RH (Tagawa et al., 1994; Joannides et al., 1995; Engelke et al., 1996; Dakak et al., 1998), these findings are equivocal (Bank et al., 2000; Crecelius et al., 2013). Further, in the studies that found an influence of NO on RH, the specific temporal contribution has been variable. Some data suggest that NO contributes only to peak RH (Engelke et al., 1996), only to the RH AUC (Tagawa et al., 1994; Joannides et al., 1995), or to both RH phases (Dakak et al., 1998). Given the equivocal findings in these previous studies, more recent mechanistic insight has aimed to uncover the pathways contributing to RH. Using forearm occlusion plethysmography and intrabrachial drug infusions, Crecelius et al. (2013) previously demonstrated that NO and prostaglandins contribute minimally to post-occlusion RH. Rather, it appeared that the activation of inwardly-rectifying K+ channels and Na+/K+-ATPase was the primary contributor to peak and AUC RH.

In the scope of the present study, it appears that BL sex differences in RH depend on the measure (i.e., velocity versus flow), rather than the temporal response (i.e., peak versus AUC). Though the BL population typically exhibits reduced NO bioavailability (Kalinowski et al., 2004; Patik et al., 2018), the low dependence of RH on NO complicates interpretation of the present data and may suggest a few things: 1) sex differences in microvascular function may not exist in young, BL individuals; 2) RH in BL individuals, specifically, is primarily influenced by non-NO mechanisms. Regarding the second point, while there is evidence specifically outlining non-NO mechanisms for RH (Crecelius et al., 2013), there is no literature to our knowledge specifically investigating racial/ethnic or race-by-sex differences for these other controlling mechanisms in RH. Therefore, further research is needed to better understand the RH responses in the present study, the mechanisms behind them, and how they may contribute to the observed epidemiological data.

Like RH, cerebrovascular reactivity to hypercapnia appears to have a few contributing pathways. Increased arterial CO2 ultimately reduces blood pH, leading to cerebral vasodilation and robust increases in cerebral blood flow (Brian Jr et al., 1996; Ainslie & Duffin, 2009). This vasodilation is, at least partially, mediated by NO (Schmetterer et al., 1997). During hypercapnia, however, NO may act indirectly and serve as a permissive molecule for other cerebral vasodilators. Indeed, NO-inhibition reduces cerebral blood flow at rest and during hypercapnia, the latter of which may be side-effect of reductions in the efficacy for other molecules to elicit vasodilation (Iadecola & Zhang, 1996). This may be of particular importance in the BL population, as reductions in NO bioavailability may reduce overall cerebral vasodilation through this synergistic mechanism. Beyond active vasodilation, augmented sympathetic nerve activity (SNA) may attenuate hypercapnia-induced vasodilation, ultimately dampening the typical increases in cerebral blood flow. Previous data from Jordan et al. (2000) suggest that increases in SNA blunt the relation between ΔPETCO2 and ΔVMCA. As young, BL individuals exhibit augmented sympathetic reactivity relative to young, WH individuals (Calhoun et al., 1993; Ray & Monahan, 2002), any hypercapnic vasodilation may be attenuated by this SNA. Remarkably, augmented sympathetic reactivity may not be consistent between BW and BM, as BW seemingly have similar sympathetic reactivity as WH women (Jarvis et al., 2014).

Experimental Considerations

While this study presents preliminary data highlighting unique sex differences in vascular function in the young, BL population, there are considerations that should be made when interpreting these data. First, sex hormones can exert strong influences on vascular function (Hashimoto et al., 1995; Stanhewicz et al., 2018), which may be causing the observed sex differences. The women in this study were tested during a low hormone phase (see Table 1). Therefore, given the typical augmentation in vascular function during the high hormone phase of the menstrual cycle, we may be underestimating differences in peripheral and cerebral vascular reactivity. Second, the use of TCD to estimate changes in cerebral blood flow is limited by its inability to measure vessel diameter. Given the hypercapnic challenge in the present study, TCD may still be a valid approach for assessing cerebral hemodynamics (Ainslie & Duffin, 2009). Interpretation of these data, however, may become more challenging at greater ΔPETCO2, whereby changes in vessel diameter might lead to underreporting of cerebral hemodynamic changes (Ainslie & Hoiland, 2014). In this regard, it may be that the differences in CVR between BM and BW are underestimated at high ΔPETCO2, though the results at lower ΔPETCO2 (i.e., < Δ9 mmHg) remain valid. Third, we did not include a reference group (e.g., WH) in this study as the scope of this research was focused solely on sex differences within the BL population. Given the extensive body of research demonstrating independent racial/ethnic or sex differences in vascular function (Celermajer et al., 1994; Perregaux et al., 2000; Gokce et al., 2001; Campia et al., 2002; Nishiyama et al., 2008b; Hurr et al., 2015; Patik et al., 2018), often including WH individuals, we aimed to assess this unique interaction between BL men and women across several vascular beds. Investigation of several vascular beds is of particular importance because differences in one vessel may not directly relate to another, particularly between the peripheral and cerebral circulations (Carr et al., 2020). Last, we did not explore the potential influence of various social determinants of health (e.g., socioeconomic status, perceived discrimination) on our observed sex differences in vascular function. Chronic elevations in social stressors are associated with augmented oxidative stress and inflammation (Irie et al., 2002; Nazmi & Victora, 2007), among other detrimental biological mechanisms, which lead to reductions in NO-mediated vascular function (Heitzer et al., 2001; Patik et al., 2018). While much of the previous research regarding these social stressors has focused on racial/ethnic differences, the additional influence of sex is an important consideration. Indeed, BL men and women seem to experience social stressors differently (Brownlow et al., 2019). Accordingly, future research should incorporate measures of social stress to better understand its impact on sex differences in Black individuals’ vascular function.

Conclusions

In conclusion, our preliminary findings suggest that young, BW exhibit disparate peripheral and cerebral vascular reactivity relative to young, BM, including augmented FMD and CVR, yet similar post-occlusive RH. These sex differences allude to mechanistic differences that may be blunting or augmenting certain indices of vascular function in young, BM and BW. Accordingly, these differences may be driving such things as the reduced age-adjusted stroke mortality, but elevated CVD prevalence in BW. Further research is needed to better understand 1) the mechanisms underlying vascular function differences between young, BW and BM, 2) how any augmented function in BW, relative to BM, deteriorates across the lifespan, and 3) how these functional disparities at a young age contribute to CVD development in later life.

Supplementary Material

supinfo

New Findings.

What is the central question of the study?

Does peripheral and cerebral vascular function differ in young, non-Hispanic Black men and women?

What is the main finding and its importance?

The non-Hispanic, Black women in this study presented greater peripheral conduit artery and cerebrovascular reactivity, yet similar peripheral microvascular function relative to the non-Hispanic, Black men. These preliminary findings suggest that young, Black women and men possess divergent vascular function, possibly contributing to the unique non-Hispanic Black sex differences in cardiovascular and cerebrovascular diseases.

Acknowledgments

The authors would like to express our appreciation to all of our participants for their participation in this study.

Grants

This study was supported by the College of Nursing and Health Innovation at the University of Texas at Arlington.

Footnotes

Competing Interests

The authors have no Conflict(s)-of Interest/Disclosures to report.

Data Availability Statement

All raw data were collected and generated at the University of Texas at Arlington. These data supporting the findings and conclusions of this study are available from the corresponding author on request

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

supinfo
NIHMS1793209-supplement-supinfo.xlsx (56.5KB, xlsx)

Data Availability Statement

All raw data were collected and generated at the University of Texas at Arlington. These data supporting the findings and conclusions of this study are available from the corresponding author on request

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