Endothelial Function and Peripheral Artery Control - Gow

Review Vascular Tree

1. Two circuit system

2. arteries/veins are not the same because arteries take blood away from the heart and veins take blood toward the heart

3. Compliance vessels: veins 

   1. expand and hold large volumes of blood. 

   2. “Blood reservoir”

4. Resistance vessels: 

   1. arterioles control blood flow and bp.

Vessel Diameter: size, thickness, proportion of elastic and fibrous 

1. Artery: 

   1. Largest, thickest

   2. Mostly smooth and elastic, some fibrous

2. Arteriole: 

   1. 2nd largest and thickest

   2. No elastic or fibrous, just smooth muscle 

3. Capillary:

   1. Smallest, thinnest

   2. No muscle 

4. Venule: 

   1. 2nd largest, same thickness as artery

   2. Some fibrous tissue

5. Vein: 

   1. Largest, slightly thinner than artery and venule

   2. Equal amount of elastic, smooth, and fibrous tissue

Small Artery Structure

Layers from outside → inside:

1. Adventitia – outer protective layer.

2. Media – smooth muscle that changes vessel diameter.

3. Intima – inner lining touching the blood.

4. Elastic lamina (internal/external) – stretchy layers helping arteries expand and recoil.

Arteries are structured to withstand high pressure and regulate blood flow.

Capillary Structure

• Basal lamina → supports the capillary

• Pericytes → provide stability & regulate flow

• Vesicles → move substances across the cell

• Fenestrations (pores) → allow faster movement of small molecules

• Interdigitated junctions → control what passes between cells

What is vascular pressure determined by? What does the graph show?

diameter

transmural pressure:

• P = T/r

• Aorta 170kdynes/cm

• Capillary 16 dynes/cm

Pressure (Top Graph)

• Aorta → arteries → arterioles: Pressure steadily drops

• Capillaries: Very low pressure to allow safe exchangs

• Systolic & diastolic values only meaningful in large arteries

Velocity (Bottom Graph)

• Fastest in aorta and arteries

• Slowest in capillaries (allows nutrient/gas exchange)

• Speeds up again in veins

What is fluid flow determined by?

hydrostatic pressure

due to high hydrostatic pressure in the arterioles, fluid is pushed out

oncotic pressure pulls fluid into the interstitial space

due to low hydrostatic pressure in the venules, fluid is reabsorbed into venules

(back and forth motion, vice versa)

How do we regulate vascular function?

Vascular Metabolites: CO2, K+, temp, pH, adenosine

Autoregulation: myogenic response

Endothelial Control: response to shear stress and stretch, long/short term regulation

endothelial control

prostacyclins and thromboxanes: made form arachidonic acid through COX pathway balance each other out

TXA2: produced by platelets which initiate aggregation → vasoconstriction

PGI2: produced by endothelial cells → vasodilation

Aspirin: decreases production of TXA2 and PGI2 (cardioprotective)

What is NO produced by? what are the three isoforms? What turns production on/off?

produced by Nitric Oxide Synthase (NOS)

isoforms: e, n, i

mechanisms:

• calcium-calmodulin: increase NO

• phosphorylation: both

• caveolin: decrease NO

How do we activate NOS? (→ increase NO)

neurohumoral: ACh, Histamine, bradykinin, serotonin, substance P

physical: shear stress

metabolic: NADPH (cofactor for NOS to funciton), Oxygen

What activates Nitric Oxide Synthase (NOS)?

• ↑ Calcium activates NOS

• Requires critical cofactors: heme + tetrahydrobiopterin (BH₄)

• Uses substrates: L-arginine, O₂, NADPH

• Produces: Citrulline + Nitric Oxide (NO) + NADP

What happens after nitric oxide (NO) is produced by endothelial cells?

• NO activates soluble guanylyl cyclase

• Converts GTP → cGMP

• cGMP causes smooth muscle relaxation → vasodilation

• Overall effect: blood vessel widening + improved blood flow

What decreases or interferes with NO production?

• ADMA (Asymmetric Dimethylarginine)

  • Competes with arginine → NOS uncoupling

• Oxidative stress reduces NO availability

• Nitrites and nitrates can serve as alternative NO sources (backup system)

How does hemoglobin regulate nitric oxide (NO) signaling (endocrine vs paracrine)?

• Hb can bind, carry, release, or inactivate NO depending on oxygenation state.

• Oxygenated Hb (HbO₂): bind NO → limits NO availability.

• Deoxygenated Hb: release NO-related species (RSNOs) → promote vasodil in tissues that need O2

• Hb acts as sensor:

  • High O₂ → NO trapped (paracrine inhibition)

  • Low O₂ → NO released to dilate vessels (endocrine-like signaling)

Hb helps match blood flow to metabolic demand by controlling NO activity.

Examples of Nitroprusside and Nitrates

ISDN

ISMN (5-mononitrate)

GTN

sodium nitroprusside

Examples of PDE-5 Inhibitors

Sildenafil, Varenafil, Tadalafil used treat erectile dysfunction (ED)

at high dose: treat pulmonary HT by prolonging NO fx

Endothelin (what is it, what does it promote, what is it produced by, how does it work)

21 aa vasocontrictive peptide with inotropic/chronotropic fx

promotes vascular remodeling by inducing fibrosis

produced by endothelial cells in the vascular wall

action:

• preproendothelin proteolytically cleaved

• prod big endothelin

• endothelins by ECE

• acts locally through ETA and ETB receptors (GPCRs)

Describe Dietary Control of Blood Flow

Diet Source: leafy greens, veggies

oral bacteria: nitrate → nitrite

stomach enzymes: nitrite → NO

leads to vasodilation, protection in hypoxia, host defense, recycling

What does Beet Juice improve in PAD patients?

Beet juice is rich in nitrates → increase NO in body → vasodilation

improves O2 delivery, enhancing exercise

improves response to claudication time and vascular outcomes