Microvascular β-adrenergic receptor-mediated vasodilation is attenuated in adults with major depressive disorder

Abstract

Background:

Major depressive disorder (MDD) is associated with sympathetic overactivity and alterations in peripheral adrenergic receptor function; however, no studies have directly assessed vasoconstrictor responsiveness in adults with MDD. We tested the hypotheses that β-adrenergic receptor-mediated vasodilation would be blunted in adults with MDD compared to healthy non-depressed adults (HA) and would functionally contribute to exaggerated norepinephrine (NE)-induced vasoconstriction.

Methods:

In 13 HA (8 female; 24±4 yrs) and in 12 adults with MDD (8 female; 22±3 yrs), red blood cell flux was measured during graded intradermal microdialysis perfusion of the β-adrenergic receptor agonist isoproterenol (10⁻¹⁰ to 10⁻⁴ mol/L) and, separately, during the perfusion of NE (10⁻¹² to 10⁻² mol/L), alone and in combination with the β-adrenergic receptor antagonist propranolol (2 mmol/L). Non-adrenergic vasoconstriction was assessed via perfusion of angiotensin II (10⁻¹² to 10⁻⁴ mol/L).

Results:

Isoproterenol-induced vasodilation was blunted in adults with MDD (188.9±70.1 HA vs. 128.3±39.4 au MDD, p=0.025). Net NE-induced vasoconstriction was exaggerated in adults with MDD (−0.16±0.54 HA vs. −0.75±0.56 au MDD, p=0.014); however, there were no group differences in angiotensin II-induced vasoconstriction. Propranolol potentiated NE-induced vasoconstriction in HA (−0.16±0.54 NE vs. −1.60±1.40 au propranolol, p<0.01), but had no effect in adults with MDD (−0.75±0.56 NE vs. −1.58±1.56 au propranolol, p=0.08).

Conclusions:

β-adrenergic receptor-mediated microvascular vasodilation was blunted in adults with MDD and contributed to exaggerated adrenergic vasoconstriction. The relative loss of the vasoprotective effect of β-adrenergic receptor-mediated vasodilation may contribute to increased peripheral resistance, thereby driving the development of hypertension in adults with MDD.

INTRODUCTION

Major depressive disorder (MDD) is an episodic and highly recurrent mood disorder, characterized by persistently depressed mood and/or anhedonia that causes significant functional impairment in everyday life and manifests in ~15% of adults across their lifespan.^{1, 2} In addition to its debilitating effects on mood and behavior, MDD is also directly linked to the excessive (~3x greater risk) and premature (~8 yrs earlier) development of cardiovascular disease (CVD),³ an association that persists even in patients with remitted depressive symptoms.⁴ Although the mechanisms underlying MDD-CVD comorbidity remain incompletely understood, one plausible contributor is the disruption of vascular homeostasis, such that increased vasoconstrictor tone predominates (concomitant with a reduction in vasodilatory capacity), thereby driving the development of hypertension and attendant CVD sequalae in adults with MDD.⁵

In the vasculature, norepinephrine (NE) is released from sympathetic varicosities into the synaptic cleft and binds to both α- and β-adrenergic receptors located on the vascular smooth muscle to induce vasoconstriction and vasodilation, respectively. While the vasoconstrictor response primarily governs the autonomic maintenance of cardiovascular homeostasis, β-adrenergic receptor-mediated vasodilation, a largely endothelium-dependent process, functions to partially restrain α-adrenergic receptor-mediated vasoconstriction^{6, 7} Blunted β-adrenergic receptor-mediated vasodilation is evident in adults at increased risk for developing hypertension (e.g., Black men, postmenopausal women)^7-13 The relative loss of the vasoprotective effect of β-adrenergic receptor-mediated vasodilation to counterbalance excessive sympathetic vasoconstriction may augment total peripheral resistance and impair blood pressure regulation, thereby contributing to increased CVD risk⁷ Although MDD is associated with tonic sympathetic hyper-activity,^{14, 15} no studies have directly assessed vasoconstrictor responsiveness in adults with MDD, and the limited evidence for exaggerated sympathetic vasoconstriction from rodent models of depression is equivocal^{16, 17} However, alterations in peripheral adrenergic receptor function are evident in adults with depressive mood disorders, with studies consistently reporting increased α- and decreased β-adrenergic receptor sensitivity in circulating lymphocytes and platelets^18-24 Despite profound reductions in vasodilatory capacity in adults with depression,^25-30 whether blunted vascular β-adrenergic receptor-mediated vasodilation is evident, and mechanistically contributes to potentiated NE-induced vasoconstriction, has not been examined.

The purpose of this investigation was to examine microvascular β-adrenergic receptor function in non-medicated otherwise healthy adults with MDD. We hypothesized that vasodilation in response to selective agonism of β-adrenergic receptors would be blunted in adults with MDD compared to healthy non-depressed adults (HA). We also assessed microvascular responsiveness to NE and hypothesized that the functional β-adrenergic receptor-mediated component of NE-induced vasoconstriction would be reduced in adults with MDD.

METHODS

The data that support the findings of this study are available upon reasonable request. The Institutional Review Board at The University of Texas at Arlington approved the experimental procedures (2019-0266). The study was conducted in accordance with the guidelines set forth by the Declaration of Helsinki, except for registration in a database. Verbal and written informed consent were obtained voluntarily from all participants prior to participation. A detailed Methods section is available in the Online Supplement.

Adults with MDD were classified using the Mini-International Neuropsychiatric Interview (MINI) diagnostic algorithm (n=12, 8 female; Table 1).³¹ Healthy non-depressed adults (n=13, 8 female) did not have any history or evidence of major psychiatric illness and served as the control group. Depressive symptom severity was evaluated by the Patient Health Questionnaire-9 (PHQ-9) and the National Institutes of Health (NIH) Patient-Reported Outcomes Measurement System (PROMIS; emotional distress – depression, short-form).^32-34 The assessment of microvascular function occurred within ~1 week of study enrollment to facilitate expedient follow-up with a mental healthcare provider and thus did not control for menstrual cycle phase (for review, see³⁵).

Table 1.

Subject Characteristics.

Characteristic	HA	MDD	p-value
N (M/F)	13 (5/8)	12 (4/8)
Age (yr)	24 ± 4	22 ± 3	0.09
Height (cm)	170.0 ± 12.5	164.3 ± 8.1	0.19
Mass (kg)	75.9 ± 19.3	63.1 ± 14.1	0.07
BMI (kg/m2)	25.8 ± 3.6	22.1 ± 2.7	0.10
Heart Rate (bpm)	78 ± 14	73 ± 11	0.39
Systolic BP (mmHg)	119 ± 11	117 ± 9	0.75
Diastolic BP (mmHg)	76 ± 5	76 ± 6	0.95
Habitual Physical Activity (MET-mins/wk)	9,190 ± 9,852	5,991 ± 7,258	0.39
Blood Biochemistry
HbA1c (%)	5.3 ± 0.3	5.2 ± 0.2	0.61
Total Cholesterol (mg/dl)	177 ± 24	171 ± 25	0.63
HDL (mg/dl)	58 ± 17	62 ± 10	0.78
LDL (mg/dl)	101 ± 26	93 ± 26	0.53
Triglycerides (mg/dl)	95 ± 32	84 ± 43	0.94
Depression Assessment
PHQ-9 (au)	2 ± 2	10 ± 7 *	<0.01
PROMIS (raw score)	11 ± 3	24 ± 8 *	<0.01
PROMIS (T-score)	46 ± 7	62 ± 6 *	<0.01
Emotional Assessment
Negative Affect (T-score)	42 ± 6	66 ± 9 *	<0.01
Social Satisfaction (T-score)	53 ± 6	37 ± 9 *	<0.01
Psychological Well-Being (T-score)	57 ± 7	43 ± 7 *	<0.01

HA, healthy non-depressed adults; MDD, Major Depressive Disorder; BMI, body mass index; BP, blood pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PROMIS, patient-reported outcome measurement information system; PHQ-9, Patient Health Questionnaire (symptom severity: 0-4, minimal; 5-9, mild; 10-14, moderate; 15-19, moderately severe; 20-27, severe); PROMIS, patient-reported outcome measurement information system. Emotional Assessments were derived from the NIH Toolbox. Values are mean ± standard deviation.

^*P<0.05 v. HA.

Assessment of Microvascular β-adrenergic Receptor Function

Using sterile technique, intradermal microdialysis probes (CMA Linear 30 probe, 6 kDa; Harvard Apparatus, Holliston, MA, USA) were inserted into the dermal layers of the ventral forearm for the local delivery of pharmacological agents (see Online Supplement).^{26, 27, 36} Red blood cell flux, an index of cutaneous blood flow, was continuously measured directly over each microdialysis probe using an integrated laser Doppler flowmeter probe secured in a local heating unit set to thermoneutrality (33°C; VP12 and VHP2; Moor Instruments, Wilmington, DE, USA). Brachial artery blood pressure (Connex Spot Monitor) was measured every 4 min throughout the protocol.

β-adrenergic receptor-mediated vasodilation was assessed by perfusion of ascending concentrations of non-specific β-adrenergic receptor agonist isoproterenol (10⁻¹⁰ to 10⁻⁴ mol/L; United States Pharmacopeia (USP), Rockville, MD, USA). Following the dose-response protocol, maximal dilation was elicited using concurrent sodium nitroprusside (28 mmol/L; USP) perfusion and local heating (43°C). Separately, ascending concentrations of NE (10⁻¹² to 10⁻² mol/L; USP) were perfused alone and during concurrent perfusion of the non-selective β-adrenergic receptor antagonist propranolol (2 mmol/L; USP) and the non-selective α-adrenergic receptor antagonist phentolamine (314.7 μmol/L; Santa Cruz Biotechnology, Dallas, TX, USA). In a subset of participants (n=8 HA, n=4 MDD), the selective α₂-adrenergic receptor antagonist yohimbine (5 mmol/L; USP) was perfused instead of phentolamine. There were no differences between the effects of phentolamine and yohimbine on NE-induced vasoconstriction (P=0.11); therefore, the data at these two sites were pooled. Non-adrenergic vasoconstriction was assessed by perfusion of progressively increasing doses of angiotensin II (10⁻¹² to 10⁻⁴ mol/L; Tocris Bioscience, Ellisville, MO, USA).³⁷

Data and Statistical Analysis

Red cell flux was recorded at 40 Hz (PowerLab and LabChart; ADInstruments, Colorado Springs, CO, USA) and stored for offline analysis. Vascular conductance was calculated as laser Doppler flux (perfusion units) divided by mean arterial pressure and was averaged during 5 min of baseline and during the last min of each dose.^{6, 26, 27, 37-39} In Protocol 1, data were normalized and expressed as a percentage of maximum vascular conductance (%CVC_max).^{26, 27} In Protocols 2 and 3, data were normalized and expressed as an absolute change from baseline vascular conductance (ΔCVC_base).⁴⁰ Area under the dose-response curve (AUC) was calculated using the trapezoid rule and used as an index of the cumulative effect of the pharmacological substance (Prism v8.1; GraphPad Software, LaJolla CA, USA). Because NE administration to the cutaneous microvasculature elicits a biphasic response,^{6, 38, 39} the net AUC was calculated as differences between the area above baseline and the area below (net AUC = AUC above the baseline – AUC below the baseline).

Our sample size of 12 participants per group allowed us to detect a meaningful physiological difference (Cohen’s f = .25) with 80% power. Student’s unpaired t-tests were used to compare subject characteristics. Vascular conductance and AUC were analyzed using two-way and three-way mixed-model ANOVAs (SAS v9.4; Cary, NC, USA), with post hoc Tukey corrections applied for specific planned comparisons when appropriate. Data are presented as mean±standard deviation and significance was set to α<0.05.

RESULTS

There were no group differences in age, anthropometry, resting blood pressure and heart rate, or blood biochemistry (Table 1; all P>0.05). Adults with MDD were experiencing a major depressive episode of mild-to-moderate severity (Table 1; all P<0.05). In addition, indices of overall emotional health and well-being were lower and negative affect was greater in adults with MDD compared to HA (Table 1; all P<0.05).

β-adrenergic receptor-mediated vasodilation is blunted in adults with MDD

There were no differences in either baseline (Table 2; P=0.36) or maximal vascular conductance (1.63±0.69 HA vs. 2.29±0.99 PU/mmHg MDD, P=0.08) between groups. Isoproterenol elicited a modest concentration-dependent vasodilatory response in both HA and in adults with MDD; however, isoproterenol-induced vasodilation was blunted in adults with MDD (Fig. 1; P<0.05).

Table 2.

Baseline Vascular Conductance.

Pharmacological Treatment	HA	MDD
Isoproterenol	0.14 ± 0.04	0.17 ± 0.11
NE	0.16 ± 0.09	0.27 ± 0.11
Propranolol	0.66 ± 0.50	0.41 ± 0.31
Phentolamine/Yohimbine	0.14 ± 0.04	0.37 ± 0.21
Angiotensin II	0.25 ± 0.15	0.30 ± 028

HA, healthy non-depressed adult; MDD, major depressive disorder; NE, Norepinephrine; CVC, cutaneous vascular conductance. Vascular conductance was calculated as flux (perfusion units) · mean arterial pressure (mmHg)⁻¹. Data were analyzed via two-way mixed-model ANOVA (group: P=0.79; drug: P<0.01; interaction: P=0.02). Values are mean ± SD.

Figure 1.

Isoproterenol-induced vasodilation is blunted in adults with major depressive disorder (MDD). Vascular conductance in response to increasing doses of isoproterenol (Panel A) and as area under the dose-response curve (Panel B) in healthy non-depressed adults (HA; n=13, 8 female) and in adults with MDD (n=12, 8 female). Data were analyzed via two-way mixed-model ANOVA and presented as mean±standard deviation (Panel A) or via unpaired t-tests and presented as box plots with mean±95% confidence intervals (Panel B). CVC, cutaneous vascular conductance; au, arbitrary units. *p<0.05 vs. HA.

NE-induced vasoconstriction is exaggerated in adults with MDD

There were no group differences in baseline vascular conductance (Table 2; P=0.79). Perfusion of NE elicited a biphasic response in both groups such that low concentrations elicited a small increase (~50% of baseline) in vascular conductance, whereas higher concentrations caused progressive and robust vasoconstriction (Fig. 2A). The net vasoconstrictor response elicited by NE was augmented in adults with MDD (Fig. 2A-B; both P<0.05). In contrast, there were no group differences in angiotensin II-induced vasoconstriction (Fig. 2C-D; both P>0.05).

Figure 2.

Net norepinephrine (NE)-induced vasoconstriction is exaggerated in adults with major depressive disorder (MDD). Vascular conductance in response to increasing doses of NE (Panel A) and angtiotensin II (Panel C) and as area under the dose-response curve (AUC; Panels B, D) in healthy non-depressed adults (HA; n=13, 8 female) and in adults with MDD (n=12, 8 female). The net AUC was calculated as differences between the area above baseline and the area below (net AUC = AUC above the baseline – AUC below the baseline). Data were analyzed via two-way mixed-model ANOVA and presented as mean±standard deviation (Panels A, C) or via unpaired t-tests and presented as box plots with mean±95% confidence intervals (Panels B, D). CVC, cutaneous vascular conductance; au, arbitrary units. *p<0.05 vs. HA.

The β-adrenergic receptor-mediated contribution to NE-induced vasoconstriction is attenuated in adults with MDD

There were differences in baseline vascular conductance between pharmacological treatment sites (Table 2; P<0.01) but not between groups (Table 2; P=0.79). In HA, co-perfusion of propranolol potentiated NE-induced vasoconstriction (Fig. 3A-B; both P<0.01). However, the effect of propranolol on NE-indueced vasoconstriction was functionally absent in adults with MDD (Fig. 3C, interaction P=0.98; Fig. 3D, P=0.0679). In both HA (Fig. 4A, interaction P<0.001; Fig. 4B, P=0.005) and adults with MDD (Fig. 4C, interaction P<0.001; Fig. 4D, P=0.006), co-perfusion of phentolamine/yohimbine eliminated NE-induced vasoconstriction. When vascular conductance was normalized as a percentage of the site-specific baseline, similar results were obtained (data not shown).

Figure 3.

The functional contribution of β-adrenergic receptor-mediated vasodilation to restrain norepinephrine (NE)-induced vasoconstriction is absent in adults with major depressive disorder (MDD). Vascular conductance in response to increasing doses of NE (Panels A, C) and as area under the dose-response curve (AUC; Panels B, D) alone (CON) and during concurrent perfusion of the non-selective β-adrenergic receptor antagonist propranolol (PROP) in healthy non-depressed adults (HA; n=13, 8 female) and in adults with MDD (n=12, 8 female). The net AUC was calculated as differences between the area above baseline and the area below (net AUC = AUC above the baseline – AUC below the baseline). Data were analyzed via two-way mixed-model ANOVA and presented as mean±standard deviation (Panels A, C) or as box plots with mean±95% confidence intervals (Panels B, D). CVC, cutaneous vascular conductance; au, arbitrary units.

Figure 4.

Antagonism of α-adrenergic receptors functionally eliminates norepinephrine (NE)-induced vasoconstriction in adults with major depressive disorder (MDD). Vascular conductance in response to increasing doses of NE (Panels A, C) and as area under the dose-response curve (AUC; Panels B, D) alone (CON) and during concurrent perfusion of the non-selective α-adrenergic receptor antagonist phentolamine or yohimbine (PHEN/YOH) in healthy non-depressed adults (HA; n=13, 8 female) and in adults with MDD (n=12, 8 female). The net AUC was calculated as differences between the area above baseline and the area below (net AUC = AUC above the baseline – AUC below the baseline). Data were analyzed via two-way mixed-model ANOVA and presented as mean±standard deviation (Panels A, C) or as box plots with mean±95% confidence intervals (Panels B, D). CVC, cutaneous vascular conductance; au, arbitrary units.

DISCUSSION

The novel findings of the present investigation demonstrate attenuated β-adrenergic receptor-mediated microvascular vasodilation in young otherwise healthy adults with MDD. In addition, adrenergic vasoconstriction was exaggerated in adults with MDD and mediated, at least in part, by a functional loss of β-adrenergic receptor-mediated vasodilation. Taken together, these data support the hypothesis that a relative loss of β-adrenergic receptor-mediated vasodilation to offset α-adrenergic receptor-mediated vasoconstriction may contribute to a pro-constrictor microvascular milieu in adults with MDD. Collectively, these findings, which are the first direct evidence of heightened vasoconstrictor responsiveness in adults with MDD, add to the growing body of literature demonstrating marked alterations in the mechanisms regulating microvascular function in adults with depressive mood disorders^25-30 and suggest a potential mechanism linking depression to increased risk of the development of future hypertension and overt CVD.

In the cutaneous microcirculation, there is evidence for functional β-adrenergic receptors,⁴¹ and direct agonism with isoproterenol administration via intradermal microdialysis elicits vasodilation (~50-60% of maximal conductance) in healthy adults.^{42, 43} The vasodilatory response to isopreoterenol perfusion was of a similar magnitude in the healthy non-depressed adults in the present study. Although isoproterenol also induced vasodilation in adults with MDD, the magnitude of the response was markedly blunted compared to that in HA, providing the first direct evidence of reductions in microvascular β-adrenergic receptor sensitivity. In circulating lymphocytes and platelets isolated from patients with depressive mood disorders, isoproterenol-stimulated cyclic adenosine monophosphate production is blunted compared to that in healthy adults, indicative of reductions in peripheral β-adrenergic receptor sensitivity.^18-24 The present data are both consistent with, and an extension of, this work.

Blunted vasodilation in response to isoproterenol has also been observed in the forearm vasculature in young (~30 yrs) Black men and young adults with prehypertension,^{8, 9, 12} as well as in older women and overweight adults^{7, 10, 11, 13}—all clinical populations with a substantially increased risk for future hypertension.^{8, 9, 12} Importantly, in some of these studies,^{8, 10, 13} impairments in β-adrenergic receptor-mediated vasodilation were observed in the absence of elevated blood pressure, suggesting that reduced vascular β-adrenergic sensitivity may precede the development of hypertension. In addition to the direct action on vascular smooth muscle cell β-adrenergic receptors, isoproterenol also elicits vasodilation via endothelium-dependent nitric oxide-mediated signaling pathways.⁴⁴ Although we did not specifically quantify the magnitude of the nitric oxide-dependent component of isoproterenol-induced vasodilation in this study, based on our previous findings indicating a blunted nitric oxide-dependent component of both acetylcholine- and paroxetine-induced vasodilation in young adults with MDD,^{26, 27} we speculate that reductions in microvascular nitric oxide bioavailability likely contribute to the findings observed herein. Given that a loss of nitric oxide-mediated signaling contributes to altered mechanistic control of isoproterenol-induced vasodilation in overweight adults,⁴⁵ future studies determining the molecular underpinnings of attenuated β-adrenergic receptor-mediated vasodilation in adults with MDD are warranted. Nevertheless, in addition to the potential implications for blood pressure regulation, attenuated isoproterenol-induced vasodilation in adults with MDD adds to the growing body of literature demonstrating reduced cutaneous microvascular vasodilatory responsiveness to agonists that activate multiple downstream signaling pathways,^{26, 27, 36} thus providing additional mechanistic support for microvascular endothelial dysfunction as a hallmark of MDD.

The functional consequences of reduced peripheral microvascular β-adrenergic receptor sensivity are likely most important for mitigating sympathetically mediated vasoconstriction and thus preventing untoward increases in blood pressure.⁴⁶ Although MDD is associated with increased basal sympathetic outflow,^{14, 15} to our knowledge, no studies have examined vasoconstrictor responsiveness in adults with MDD. In rodent models of depression, there is some evidence for exaggerated phenylephrine-induced vasoconstriction¹⁶ but this finding is not universal.¹⁷ In the present study, and similar with previous investigations utilizing the cutaneous microcirculation,^{6, 38, 39} NE elicited a similar profile of vascular responsiveness in both groups: β-adrenergic receptor-mediated dilation was evident at lower concentrations with a concentration-dependent progressive increase in α-adrenergic receptor-mediated vasoconstriction, such that the overall net response to NE perfusion was vasoconstriction. However, the net vasoconstrictor response to NE was exaggerated in adults with MDD. Excessive agonist-induced vasoconstriction was only observed in response to adrenergic activation, as there were no differences in angiotensin II-induced vasoconstriction between HA and adults with MDD.

In non-depressed young adults, we observed a role for β-adrenergic receptors to offset NE-induced vasoconstriction. That is, during perfusion of propranolol to inhibit the vasodilatory influence of β-adrenergic receptors, there was a large increase in net NE-induced vasoconstriction. However, in adults with MDD, concurrent β-adrenergic receptor inhibition had minimal-to-no effect on the net vasoconstrictor response to NE. In both groups, antagonism of α-adrenergic receptors completely eliminated NE-constriction. Perhaps surprisingly, the magnitude of vascular responsiveness to NE in the presence of α-adrenergic receptor inhibition was not different between groups. However, when considered collectively with blunted isoproterenol-induced vasodilation, these data suggest that the relative contribution of β-adrenergic receptor-mediated vasodilation to partially offset α-adrenergic vasoconstriction is significantly reduced in adults with MDD. These findings are consistent with prior work demonstrating that concurrent antagonism of β-adrenergic receptors substantially potentiates NE-induced forearm vasoconstriction in young women—a population demonstrated as having augmented β-adrenergic receptor-mediated blunting of sympathetic vasoconstriction—but has no effect in men or postmenopausal women.^{7, 12, 47} It is important to note that in the present study, the sex distribution was matched between groups, suggesting that a loss of the vasoprotective effect of β-adrenergic receptor-vasodilation in adults with MDD likely cannot be attributed to potential sex differences in responsiveness.

Importantly, β-adrenergic receptor function also has implications for sympathetic control of blood pressure at rest. In study above,⁷ the investigators directly measured muscle sympathetic nerve activity at rest to quantify basal sympathetic outflow, in addition to their assessment of forearm vascular β-adrenergic receptors to NE-induced vasoconstriction. They noted that β-adrenergic receptor antagonism in young women revealed a positive linear relation between muscle sympathetic nerve activity and mean arterial pressure, providing further support for the concept that vascular β-adrenergic receptors are fundamental to resting blood pressure regulation.⁷ Only one study has measured muscle sympathetic nerve activity in adults with depression, reporting profound increases in resting sympathetic activity.¹⁴ Our data raise the possibility that tonic NE release from postganglionic sympathetic fibers may not be adequately buffered by vascular β-adrenergic receptor-mediated vasodilation in adults with MDD. However, whether sympathetic outflow at rest is directly transduced to heightened vasoconstriction, and contributes to subsequent increases in blood pressure and elevated CVD risk in adults with MDD, merits future investigation.

Limitations

Several experimental considerations warrant discussion. First, the present study included both males and females in both HA and MDD groups. Although there is some evidence for sex differences in the degree of modulation of NE-induced vasoconstriction by β-adrenergic receptors,⁷ others report a lack of sex differences in isoproterenol-induced vasodilation.^{45, 48} The present study is not powered to evaluate potential sex differences; however, post hoc analyses indicate no differences in either isoproterenol-induced vasodilation (HA P=0.84, MDD P=0.44) or the effect of propranolol on NE-induced vasoconstriction between sexes in either group (HA P=0.74, MDD P=0.84). Given the small sample sizes, these data should be interpreted cautiously. Prospective studies designed to specifically examine sex differences and incorporating experimental controls for female sex hormones in larger cohorts are necessary. We also acknowledge the non-selectivity of the adrenergic receptor agonists and antagonists utilized in the present investigation. The dilatory response to isoproterenol is primarily β₂-adrenergic receptor-dependent,¹⁰ supporting the likelihood that the results here are consistent with MDD-associated reductions in β₂-adrenergic receptor sensitivity. Further, postjunctional α₁- and α₂-adrenergic adrenergic receptors are functional in the cutaneous circulation, and, in the forearm, vasoconstriction in response to preferential activation of a single receptor subtype does not differ from that elicited by NE.⁴³ Last, we conducted an effect size analysis (partial eta squared, η²_p), confirming that the group differences in isoproterenol-induced vasodilation (η²_p=0.226) and NE-induced vasoconstriction (η²_p=0.246) have a large effect size, despite the small sample size.

Perspectives

The cutaneous microvasculature primarily subserves thermoregulation, with little contribution to BP regulation at thermoneutrality. However, multiple studies have demonstrated that cutaneous microvascular function is reflective of renal and coronary microvascular function, as well as in large conduit arteries.^49-51 Moreoever, the decrements in microvascular function associated with CVD are thought to first appear in the cutaneous microcirculation, long before end-organ dysfunction becomes clinically apparent.⁵² Indeed, in >90% of patients with essential hypertension, the earliest indication of microvascular dysfunction appeared in the skin capillaries and thereafter in the retina and skeletal muscle.⁵² Thus, the alterations in mechanistic control of the cutaneous microcirculation may be among the earliest biomarkers indicative of systemic vascular dysfunction, with important downstream implications for CVD progression.

Consistent with this notion, the findings here demonstrate that β-adrenergic receptor-mediated vasodilation is attenuated in young adults with MDD and functionally contributes to exaggerated NE-induced vasoconstriction. These data support the concept that a relative loss of β-adrenergic receptor-mediated vasodilation to offset excessive α-adrenergic receptor-mediated vasoconstriction contributes to the disruption of vascular homeostasis. The clinical importance of this is underscored by the intimate link between MDD and stress system dysfunction.⁵³ Stress exposure is a powerful activator of the sympathetic nervous system and, when coupled with dysregulated microvascular adrenergic receptor function, stress-induced increases in circulating NE may set in motion a series of events that initiate and then propagate vascular damage, the effects of which may be further accelerated in adults with MDD. In this context, the findings of this investigation provide an experimental basis for designing interventional studies targeting adrenergic receptors to improve microvascular health, thereby reducing the CVD risk profile in adults with MDD.

PATHOPHYSIOLOGICAL NOVELTY AND RELEVANCE.

What is new?

• β-adrenergic receptor-mediated microvascular vasodilation was attenuated in young otherwise healthy adults with MDD.

• Further, adrenergic vasoconstriction was exaggerated in adults with MDD and mediated by a functional loss of β-adrenergic receptor-mediated vasodilation.

What is relevant?

• These data suggest that a relative loss of β-adrenergic receptor-mediated vasodilation to offset α-adrenergic receptor-mediated vasoconstriction may contribute to a pro-constrictor microvascular milieu and increased peripheral resistance in adults with MDD, thereby driving the development of hypertension in adults with MDD.

Clinical/Pathophysiological Implications

• These findings are the first direct evidence of heightened vasoconstrictor responsiveness in adults with MDD, and suggest a potential mechanism linking depression to increased risk of the development of future hypertension and overt CVD.

NONSTANDARD ABBREVIATIONS

AUC

area under the dose-response curve

CVC

cutaneous vascular conductance

CVD

cardiovascular disease

HA

healthy adult

MDD

major depressive disorder

NE

norepinephrine

PHQ-9

Patient Health Questionnaire-9

PROMIS

Patient-Reported Outcomes Measurement System