1. Ingeniería

Supporting Information
Dabertrand et al. 10.1073/pnas.1420765112
SI Materials and Methods
Diameter Measurements. After euthanasia, the brain was removed
and placed into chilled (4 °C) Mops-buffered saline. Intraluminal
pressures of 60 mmHg and 40 mmHg were used for PCAs and
PAs, respectively, unless stated otherwise. Both PCAs and PAs
were superfused (4 mL/min) with prewarmed (36 °C ± 1 °C),
gassed (gas composition, vol/vol: 5% CO2, 20% O2, 75% N2)
artificial cerebrospinal fluid (aCSF) for at least 45 min. Only
viable PCAs and PAs, defined as those that developed pressureinduced myogenic tone greater than 15%, were used in subsequent experiments. Endothelial function was tested by assessing
the vasodilator response to NS309 (1 μM), an activator of endothelial SK and IK channels. Drugs were applied by addition to the
superfusate. Changes in arterial diameter were calculated as the
percentage of change from baseline (initial diameter). Maximal
dilation was obtained in nominally Ca2+-free aCSF (0 mM [Ca2+]o,
5 mM EGTA, 100 μM papaverine).
Third-order mesenteric arteries (∼100 μm internal diameter)
were isolated into Hepes–physiological saline solution (HepesPSS), mounted on similar-sized glass pipettes in an organ chamber, and pressurized as described for PCAs. Arteries were pressurized to 80 mmHg for at least 45 min in prewarmed (36 °C ±
1 °C), gassed (gas composition, vol/vol: 5% CO2, 20% O2, 75%
N2) PSS. Only arteries that exhibited myogenic constriction to
pressure were used in experiments. Changes in arterial diameter
were calculated as the percentage of change from baseline (initial
diameter). Maximal dilation was obtained in nominally Ca2+-free
PSS (0 mM [Ca2+]o, 5 mM EGTA, 100 μM papaverine).
Arteriolar Smooth Muscle Membrane Potential Recordings. PAs were
isolated, mounted, and pressurized (10 mmHg or 40 mmHg) as
described above. Myocytes were then impaled with glass microelectrodes filled with 0.5 M KCl (tip resistance, 150–250 MΩ). A
WPI Intra 767 amplifier was used for recording membrane potential. Analog output from the amplifier was obtained using
AxoScope (Molecular Devices) software (sample frequency,
∼400 Hz). Criteria for accepting recordings were (i) an abrupt
negative deflection of potential as the microelectrode was advanced into the cell, (ii) stable membrane potential for at least
1 min, and (iii) an abrupt change in potential to ∼0 mV after
retracting the electrode from the cell. For each PA, membrane
potential was recorded in three different cells and averaged.
SMC Isolation and Perforated Patch-Clamp Experiments. Cerebral
arteries (anterior, middle, and posterior) and arterioles were
cleaned of connective tissue and placed in cell isolation solution
(see Solutions and Drugs for composition). Single SMCs were
isolated from cerebral arteries by enzymatic digestion in papain
(0.5 mg/mL) and dithioerythritol (1 mg/mL) for 12 min, followed
by a second digestion in collagenase type 4 (1 mg/mL) without
Ca2+ for 10 min. Digested tissue was washed three times and
gently triturated with a fire-polished glass pipette to release the
SMCs. The single-cell suspension of myocytes was refrigerated
until use (typically 4–6 h). Third-order mesenteric arteries were
enzymatically digested with papain (2.5 mg/mL), dithioerythritol
(1 mg/mL), and BSA for 17 min, followed by a second digestion in
collagenase type F (0.6 mg/mL) and CaCl2 (100 μM) for 6 min.
Outward K+ currents were recorded from single cells in the
presence of 1 μM paxilline (to block BK currents) at room temperature, using the perforated-cell configuration of the patchclamp technique. Recording electrodes with resistances of
Dabertrand et al. www.pnas.org/cgi/content/short/1420765112
2–4 MΩ were pulled from borosilicate glass and backfilled with
a pipette solution of appropriate composition (Solutions and
Drugs). Currents were recorded from cells using an Axopatch
200B amplifier, filtered at 2 kHz using a low-pass Bessel filter,
and digitized at 10 kHz (Digidata 1322A; Molecular Devices).
pCLAMP-9 software (Molecular Devices) was used for data recording and analysis.
NOTCH3ECD Immunohistochemistry. Mice (TgNotch3R169C, TgNotch3WT,
and Non-Tg) were overdosed with isoflurane. Second- and thirdorder mesenteric arteries were dissected under a microscope,
flash frozen in liquid nitrogen, and stored at −80 °C until use.
For immunohistochemistry, arteries were transferred to Netwell
inserts (VWR International) with an 80-μm mesh size polyester
membrane, briefly rinsed in PBS, and fixed in 100% ethanol for
20 min. After rinsing in PBS, arteries were blocked and permeabilized by incubating in a PBS solution containing 5% BSA
and 0.4% Triton X-100 for 2 h at room temperature. Arteries
were then incubated overnight at 4 °C with primary antibodies
against NOTCH3ECD (mouse monoclonal, clone 5E1) and smooth
muscle myosin heavy chain (rabbit polyclonal; Biomedical Technologies), diluted 1:2 and 1:100, respectively, in PBS/0.5% BSA.
The next day, arteries were washed with PBS and then incubated
for 2 h at room temperature with goat anti-mouse Alexa 488 and
goat anti-rabbit Alexa 594 secondary antibodies (Life Technologies) in PBS/0.5% BSA. All steps in the immunochemistry protocol
were performed with gentle shaking. Nuclei were counterstained
with DAPI (4′,6-diamidino-2-phenylindole), and arteries were
coverslip mounted on glass slides with fluorescent mounting medium (Dako). Arteries were imaged on a Nikon eclipse 80i microscope (40× oil objective, NIS elements AR Software, v4.2;
Nikon), and images were deconvolved using the AutoQuant Blind
Deconvolution plug-in for NIS elements.
Solutions and Drugs. The composition of Mops-buffered saline was
135 mM NaCl, 5 mM KCl, 1 mM KH2PO4, 1 mM MgSO4, 2.5 mM
CaCl2, 5 mM glucose, 3 mM Mops, 0.02 mM EDTA, 2 mM pyruvate, 10 mg/mL BSA, pH 7.3 (at 4 °C). The composition of
aCSF was 125 mM NaCl, 3 mM KCl, 26 mM NaHCO3, 1.25 mM
NaH2PO4, 1 mM MgCl2, 4 mM glucose, 2 mM CaCl2, pH 7.3
[with aeration with 5% (vol/vol) CO2]. The composition of
Hepes-PSS was 134 mM NaCl, 6 mM KCl, 1 mM MgCl2, 10 mM
Hepes, 7 mM glucose, 2 mM CaCl2, pH 7.4 (at 4 °C). The composition of PSS was 119 mM NaCl, 4.7 mM KCl, 24 mM NaHCO3, 1.2 mM KH2PO4, 0.026 mM EDTA, 1.2 mM MgCl2, 7 mM
glucose, 2 mM CaCl2, pH 7.4 [with aeration with 5% (vol/vol)
CO2]. The composition of cell isolation solution was 60 mM
NaCl, 85 mM Na-glutamate, 3 mM KCl, 2 mM MgCl2, 10 mM
Hepes, 10 mM glucose, 7 mM mannitol, pH 7.4. For patch-clamp
experiments using cerebral myocytes, the bath solution composition was 137 mM NaCl, 3 mM KCl, 0.1 mM CaCl2, 4 mM glucose, 10 mM Hepes (pH 7.3) and contained paxilline (1 μM); the
pipette solution was 10 mM NaCl, 30 mM KCl, 110 mM
K-aspartate, 1 mM MgCl2, 10 mM Hepes (pH 7.2) and contained
250 μg/mL amphotericin B.
Paxilline was purchased from A.G. Scientific. Apamin and
charybdotoxin were purchased from Enzo Life Sciences. Papain
and collagenase type 4 were purchased from Worthington Biochemical Corporation. All other chemicals were purchased from
Sigma-Aldrich. The vehicle for HB-EGF solutions was 0.2-μm–
filtered PBS containing 0.1% BSA.
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Fig. S1. Stromatoxin-induced vasoconstriction is not modified by the introduction of a CADASIL-causing mutation in pial arteries or parenchymal arterioles.
(A and C) Representative inner diameters recorded as a function of time from pressurized (60 mmHg) posterior cerebral arteries (A) or pressurized (40 mmHg)
parenchymal arterioles (C) before, during, and after exposure to stromatoxin (20 nM). (B and D) Bar plot showing the mean ± SEM constriction (given as
a percentage) induced by stromatoxin; the number of animals is shown in parentheses.
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Fig. S2. The 4-AP–induced constriction is increased in pial arteries from CADASIL mice. (A, a–c) Representative traces showing constriction of pial arteries
induced by the SK channel blocker apamin (300 nM), the BK channel blocker paxilline (1 μM), and the IK channel blocker charybdotoxin (100 nM). (B) Summary
data (mean ± SEM). (C, a and b) Representative traces showing constriction of pressurized (60 mmHg) pial arteries induced by the Kv channel blocker 4-AP
(1 mM) and the endothelial nitric oxide synthase (eNOS) inhibitor L-NAME (100 μM). (D) Summary data (mean ± SEM). The number of animals is shown in
parentheses. *P < 0.05, one-way ANOVA.
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Fig. S3. The 4-AP–sensitive currents are significantly increased in cerebral artery SMCs from TgNotch3R169C mice. (A) Families of normalized, 4-AP (1 mM)–
sensitive KV currents from isolated cerebral SMCs elicited by voltage pulses from −70 mV to +60 mV in the presence of 1 μM paxilline (to block BK channel
currents). (B) Graph summarizing 4-AP–sensitive current densities. Currents were normalized to cell capacitance, and values recorded in the presence of 1 mM
4-AP were subtracted from those recorded in the absence of 4-AP (*P < 0.05, one-way ANOVA).
Fig. S4. Notch3ECD accumulates in the mesenteric arteries of TgNotch3R169C mice at 6 mo of age. Shown are representative images of third-order mesenteric
arteries of 6-mo-old TgNotch3WT (A and B) and TgNotch3R169C (C and D) mice stained with anti-smooth muscle myosin heavy chain (anti-MHC) (A and C) and
anti-Notch3ECD (B and D) antibodies. The extracellular domain of Notch3 accumulates in TgNotch3R169C (D) but not TgNotch3WT (B) mesenteric arteries. (Scale
bar, 50 μm.)
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Table S1. Mean values of passive diameter (measured in the absence of extracellular Ca2+),
active diameter (after development of myogenic tone), and percentage of tone of the arteries
and arterioles used in the study
Vascular bed (pressure, mmHg)
Parenchymal arterioles (40)
Non-Tg
TgNotch3WT
TgNotch3R169C
Pial arteries (60)
Non-Tg
TgNotch3WT
TgNotch3R169C
Mesenteric arteries (80)
Non-Tg
TgNotch3WT
TgNotch3R169C
Passive diameter, μm
Active diameter, μm
Tone, %
30.6 ± 2.7
31 ± 1.8
30.3 ± 1.3
18.4 ± 1.5
19.3 ± 1.3
23 ± 1.5
39.3 ± 1.8
37.9 ± 1.8
24.4 ± 2.5*
170.1 ± 2.3
163.7 ± 3.4
150.1 ± 4.4*
120.5 ± 4.7
114.8 ± 2.3
121.8 ± 2.9
28.8 ± 1.3
27.9 ± 1.9
17.9 ± 2.4*
122.1 ± 7.2
136 ± 6.5
136 ± 7.2
96.7 ± 7.4
107.7 ± 6.6
103.4 ± 7.6
21.5 ± 2
21.3 ± 1.2
24.3 ± 2.2
*P < 0.05; one-way ANOVA followed by Tukey’s post hoc test.
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Table S2. Comparison of cerebral KV and mesenteric KV, KV1, KV2, KV3, KV4, and KV7 current properties
Current (ref.)
V0.5, mV
Slope k, mV
τact, ms
τdeact, ms
4-AP sensitive below 1 mM
Cerebral KV currents
Non-Tg
TgNotch3WT
TgNotch3R169C
6±1
3.7 ± 0.8
2.6 ± 0.6
14 ± 1
14.3 ± 0.8
15.8 ± 0.6
43 ± 3.6
34 ± 3.5
41.1 ± 6.5
28 ± 3.1
27.4 ± 3.3
26.7 ± 3.4
+
+
+
−5.7 ± 1.6
−3.7 ± 1.2
14.6 ± 1.6
14.9 ± 1.9
31.1 ± 8.8
35.3 ± 12.1
32.5 ± 2.8
29.3 ± 1.7
+
+
Mesenteric KV currents
Non-Tg
TgNotch3R169C
KV currents in
expression systems
KV1.1 (1, 2)
KV1.2 (2, 3)
KV1.3 (2)
KV1.4 (1, 4)
KV1.5 (2, 5, 6)
−32 ± 2
−5 ± 4 to 27 ± 6
−26 ± 8
−12.8 ± 3.4
−14 ± 3 to 5 ± 2.1
8.5 ± 0.5
14
14 ± 5
13 ± 2
23
23 ± 7
7±1
38
39 ± 6
13.4
15–55
NR
9.1 ± 1.7 to 12 ± 1 0.4 ± 0.1 (fast) and 15.3 ± 1.1 (fast) and
1.6 ± 0.2 (slow)
59.5 ± 5.6 (slow)
KV1.6 (7)
−20.8 ± 7.5
8.1 ± 1.5
NR
NR
KV1.7 (8)
−8
NR
NR
NR
KV1.8 (9)
3.6
NR
18
NR
KV2.1 (7, 10, 11)
−1.7,12, and 20.5
3–9.6
15.6 ± 0.9
20.9 ± 2.1
KV2.1/KV5.1 (10, 11)
18.5
17.3
20.4 ± 1.2
24.5 ± 2.3
KV2.1/KV6.1 (10, 11)
−9.4
11.8
28.2 ± 2.0
24.4 ± 0.7
KV2.1/KV6.2 (12)
−10
NR
NR
NR
KV2.1/KV6.3 (13, 14)
−13.3 ± 1.8 to −4.2 ± 0.7
9.8 ± 0.4
58 ± 5
NR
KV2.1/KV8.1 (15)
10.2 ± 0.9
NR
27.2 ± 2.5
NR
KV2.1/KV9.1 (11)
NR
NR
14.3 ± 0.8
36.4 ± 6.4
KV2.1/KV9.2 (11)
NR
NR
20.3 ± 1.3
45.2 ± 2.1
KV2.1/KV9.3 (16)
−8.7 ± 1.2
12.7 ± 1.1
NR
NR
KV2.2 (11, 17)
−16.6 ± 1.1
18
21.8 ± 0.5
39.1 ± 5.1
KV2.2/KV5.1 (11)
NR
NR
24.5 ± 2.3
130.8 ± 9.7
KV2.2/KV6.1 (11)
NR
NR
24.4 ± 0.7
147.7 ± 13.8
KV2.2/KV8.1 (15)
8.5 ± 1.4
NR
45.4 ± 3.6
NR
KV2.2/KV9.1 (11)
NR
NR
17.9 ± 0.3
27.2 ± 0.8
KV2.2/KV9.2 (11)
NR
NR
23.6 ± 1.4
43.4 ± 1.2
KV3.1 (2)
16 ± 1
8.7 ± 0.4
NR
1.4 ± 0.2
KV3.2 (6, 18, 19)
6 ± 2.4 to 12.1 ± 1.3
8.4 ± 0.3
NR
NR
KV3.3 (1, 19)
−3.4 ± 5.1 to 7
6–8.4 ± 0.4
NR
NR
KV3.4 (1, 20)
13–19
7–11
NR
NR
KV4.1 (1, 21)
−47
22
NR
NR
KV4.2 (1, 22)
−20 to −4
13–20
NR
40
KV4.3 (1, 23)
−29.1 ± 0.7 to −20
4.5–13
NR
20–40
KV7.1 (24-27)
−23.6 ± 1.6 to −18 ± 1.6
11.1–12.6
144 ± 30
621.4 ± 27 to 740
KV7.2 (24, 28, 29)
−37 ± 2 to −27.3 ± 2.4
NR
35.6 ± 5.7 and
106.7 ± 7.1 and
149.1 ± 11.8
642.3 ± 62.2
KV7.2/KV7.3 (24, 29, 30)
−40 ± 1 to −26.4 ± 2.3
6.8 ± 0.1
50.1 ± 3.4 and
144 ± 30 and 695
239.3 ± 17.5
KV7.3 (24, 29, 31)
−36 ± 1.3
5.5 ± 1.1
NR
NR
KV7.4 (24, 31)
−18.6 ± 0.3 to −0.6 ± 3.5
9.8 ± 0.2
636.3 ± 45.6
49 ± 4.2 and
350.3 ± 27.5
KV7.5 (24, 32)
−46 ± 1 to −25.1 ± 2.6
NR
37.2 ± 2.2 and
NR
247 ± 17
+
+
+
+
+
−
+
−
−
NR
NR
NR
NR
NR
NR
NR
NR
−
NR
NR
NR
NR
NR
+
+
−
+
−
−
−
−
−
−
−
NR
NR
Half-maximal activation (V0.5) voltage, slope (k), activation time constant (τact), deactivation time constant (τdeact), and 4-AP sensitivity were used as channel
fingerprints to identify the KV channel subtype involved in cerebral and mesenteric arteries. Vascular SMCs potentially express KV1–9 subtypes (19, 33, 34);
parameters of currents recorded in native myocytes point to a predominant role for the KV1 channel subfamily in both cerebral and mesenteric SMCs. NR, not
reported.
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