14. Vascular Pathophysiology

How does the body measure blood pressure?

The body senses BP as Mean Arterial Pressure (MAP) via Baroreceptors located in the aorta and carotid arteries.

What does the heart generate?

Hydrostatic pressure

What is systole?

Phase when heart muscles contracts and hows that healthy aorta is compliant.

What is Diastole?

Phase where heart muscles are relaxed and shows that healthy aorta has recoil.

What are is the function of microcirculation?

To deliver gases, nutrients, and fluid exchange between capillaries, interstitium, and lymphatics.

What determines microcirculation?

Starling-forces. Hydrostatic pressure and oncotic/osmotic pressure.

What does the starling equation determine?

The amount of filtration and absorption.

What is the starling equation?

A mathematical formula that describes the movement of fluid across capillary membranes, accounting for hydrostatic and oncotic pressures.

Jv= net filtration out of vessel (+ meaning going out to interstitium; - meaning going into BV)

Kf= vascular permeability coefficient

Pc= hydrostatic pressure in capillary

Pisf= hydrostatic pressure in interstitium

πcap= oncotic pressure in capillary

πisf= oncotic pressure in ISF

What can increase Kf /vascular permeability coefficient?

Inflammation and diabetes mellitus

What increases Pc/hydrostatic pressure of capillaries?

HTN, poor venous outflow, and local vasodilation

What decreases πcap/oncotic pressure in the capillaries?

Low protein (from malnutrition, liver disease), low salt, overhydration

What increases πisf/oncotic pressure of ISF?

Inflammation (can be systemic or local)

What are the primary etiologies of Macular Edema?

• Diabetes

• Hypertension

• Inflammation

What is used to detect macular edema?

Amsler grids

What can change capillary hydrostatic pressure?

• Artery/arteriole vasodilation

• Artery/arteriole vasoconstriction

What does artery/arteriole vasodilation cause?

• Decreases pressure in artery/arteriole

• Increases pressure in capillaries as more blood flows into capillaries

What does artery/arteriole vasoconstriction cause?

• Increases pressure in artery/arteriole

• Decreases pressure in capillaries as less blood flows into capillaries

What is lymphedema?

Edema caused by occlusion or removal of lymph nodes.

What is the pathogenesis of lymphedema?

1. Poor lymph outflow due to occlusion or removal of lymph nodes

2. Increased pressure in lymphatics

3. Fluid from lymph into ISF

4. Fluid into capillary (absorption)

What should one avoid when placing IV in?

Avoid placing IV in areas that can develop lymphedema.

How is the blood flow in blood vessels controlled?

Vascular smooth muscles in the tunica media

What regulates smooth muscles?

ANS, hormones, metabolic factors, inflammatory mediators

What smooth muscles have reciprocity?

Iris

What smooth muscles do not have reciprocity?

Blood vessels

What characteristics are unique to Smooth Muscles?

• Line hollow organs

• Not striated

• spindle-shaped

• no sarcomeres

• No troponin, just regulated myosin

What controls smooth muscle relaxation?

• NO-sensing Guanylate cyclase, cGMP, and myosin light chain phosphatase

• Activating Gs, cAMP, and inhibiting phosphorylation

What controls smooth muscle contraction?

• Activating Gq, IP3, and phosphorylating myosin light chain

What does it mean when cells are "able to latch”?

They can stay contracted without further input.

What are the types of regulation for smooth vascular muscle?

• Autoregulation: myogenic

• Local control: due to metabolic/nutrient demand or inflammation

• Systemic regulation: neural and hormonal regulation to control Blood Pressure

How does autoregulation of blood vessels work?

Mechanism not well understood, but constricts if there is an increase in blood flow and dilates if there is a decrease in blood flow.

Which regulation is able to override other regulation methods?

Local regulation, as it is the most important mechanism for meeting local metabolic demands

What metabolic factors contribute to local blood vessel regulation?

• ↓O₂

• ↑CO₂

• ↓pH (from increased metabolic activity)

• Adenosine (a by-product of ATP degradation)

How do inflammation and allergies affect local blood vessel regulation?

They promote vasodilation and increased permeability through mediators like:

• Bradykinin

• Prostaglandins

• Leukotrienes

• Histamine

How does local regulation work?

When there is a low metabolic demand, vasoconstriction causes decreased perfusion downstream. When there is a high metabolic demand, vasodilation causes increased perfusion downstream.

How does NO cause vasodilation?

1. High metabolic factors or high sheer stress (low O2, high CO2, low pH)

2. Increases cNOS (constitutive nitric oxide)

3. cNOS converts L-arginine into Nitric Oxide (NO)

4. NO diffuses into VSM

5. Increases cGMP

6. Increased MLC phosphatase

7. Dephosphorylation of myosin

8. Relaxation and vasodilation to increase blood glow

How does Inflammation cause vasodilation?

Inflammatory mediator and LPS on Gram negative bacteria causes vasodialtion via NO.

What are the mechanisms for vasodilation via inflammation?

• Inflammation

  • inflammatory factors: histamine, bradykinin, prostaglandin (PGE2, PGD2), substance P

  • increases cNOS

  • increases NO → vasodilation

  • Increased blood flow brings WBCs

• Gram negative infection

  • LPS present on Gram negative

  • Stimulates iNOS (inducible NO Synthase)

  • Increase NO → Vasodilation

  • Increased blood flow brings WBCs

What are the two main ways blood vessels control blood pressure (BP)?

• Directly by changing vessel diameter (resistance)

• Indirectly by controlling blood volume via renal vessels

How does the brain and hormones affect blood pressure?

They are mostly set up to increase BP:

• SNS activation & hormonal stimulation causes vasoconstriction, increasing BP

• SNS inhibition & hormonal inhibition causes vasodilation, decreasing BP

How does atherosclerosis and/or arteriosclerosis affect blood pressure?

• Narrows vessel lumen → increases resistance → ↑ BP

• Body compensates with vasodilation via hormones and neuron inhibition

• Treatment for hypertension: promote vasodilation, often by inhibiting vasoconstriction

What happens to blood vessels during increased and decreased SNS activity?

• ↑ SNS (α₁ receptors) → vasoconstriction

• ↓ SNS → vasodilation

How do skeletal muscle vessels respond to SNS activation?

• Vessels with β₂ receptors (e.g., in skeletal muscle) dilate during ↑ SNS activity

• This ensures increased blood flow to muscles during fight-or-flight

How is blood volume controlled?

Starling forces in the kidney regulates the volume of blood.

Vasodilation of the BV in the kidneys increases urine production, decreasing blood volume, decreasing BP.

Vasoconstriction of the BV in the kidneys decreases urine production, increasing blood volume, increasing BP.

What are the steps taken for smooth muscle contraction?

1. SNS stimulation

2. NorE or Epi binds to alpha1 adrenergic receptors to activate G1-coupled proteins (G proteins)

3. IP3 (inositol triphosphate) produced which opens calcium channels called Ryanodine receptors (RyR). May also open DHRPR

4. Calcium enters ICF from SR and/or ECF

5. Calcium binds to calmodulin (CM)

6. Calcium-calmodulin complex activates myosin light chain kinase (MLCK)

7. MLCK phsophorylates Myosin Light Chain (MLC)

8. Myosin active: crossbridge

9. Stronger stimulation causes more IP3 = stronger contraction

What biological agonists can cause vasoconstriction?

• NorE/Epi (SNS only) to alpha 1 with Gq-R and IP3 as secondary messengers

• Endocrine

  • Renin

  • Angiotensin II

  • Vasopressin

  • Endothelin-1

What biological agonists can cause vasodilation

• Atrial Natriuretic peptide (ANP) with cAMP/cGMP as second messengers and Gs-R proteins

• Adenosine on A2 receptors

• NO with cGMP as secondary messengers

What are some pathways/methods do anti-hypertensives use to reduce BP?

• Blocking calcium in smooth muscle

• inhibiting vasoconstrictors

• stimulating vasodilators

What are some calcium channel blockers that cause vasodilation?

Non-DHPR: Benzothiazepine (Diltiazem)

DHPR: Dihydropyridine (Amlodipine)

What are the types of drugs that vasodilate by inhibiting Gq?

• alpha 1 blockers: Terazosin (Hytrin)

• Renin inhibitors

• ARB (AngII Rec blocker): Losartan

• ACE inhibitor: benzapril (Lotensin)

• Vasopressin Inhibitor: Vaptan

• Endothelin Rec Blocker

• Calcium Channel Blockers: Benzothiazepine (diltiazem) and Dihydropyridine (Amlodipine)

What are the types of drugs that vasodilate by stimulation?

• ANP receptor agonists

• Adenosine receptor agonists

• Nitrodilators (increase cardiac perfusion)