Vessel Wall Biology & Atherosclerosis

1. Vessel Wall Biology &
Atherosclerosis
Dr. Muhammad Nasir
Postgraduate Resident Vascular Surgery

2. Normal Vessel Wall
 Arteries and veins have three main layers of the vessel wall.
 Intima, Media and Adventitia.
 In the arteries there are well developed layers that separate these three
compartments; internal elastic lamina (IEL) and the external elastic
lamina (EEL).
 In veins these layers are disorganized, less prominent and are difficult
to define
 Lymphatics also have these layers but they are less well defined.

3. Three main layers of the vessel wall

4. Artery
Intima:
 Innermost layer, extends from lumen to internal elastic lamina
 Very thin, lined by endothelium
 Consists of few scattered leukocytes, smooth muscle cells and
connective tissue of elastic and collagen fiber.
Endothelium:
 Cell thickness varies from 0.1 um to 100 um
 Regulator of vasomotor tone, hemostatic balance, permeability,
immunity
 Simple squamous epithelium
 Continuous layer of flat polygonal / elongated endothelial cells.

5. A Tight junctions ( zona occluden)
Barrier to the transport between ECs.
- Rigid tight junction
- Help to maintain polarity
B Adhrens junctions (zona adherens)
- Permits inter ECs communications
– movements of ions, metabolites,

6. Internal Elastic Lamina
Separates subendothelial layer from the media
Composed of elastic fibers 70-100 nm in diameter
In large arteries IEL and elastic lamellae may function as
barrier to macromolecular accumulation
Defective IEL result in abnormal attachment with ECs causing
gap – entry of macromolecules, lipids, leukocyte into intima.
Advanced plaque – fragmentation of the IEL and disruption of
medial layers.
Structural defects within IEL are directly implicated in the
onset of intimal thickening

7. MEDIA
Extends from IEL to adventitia
Is porous heterogenous medium consisting of ECM phase with
embedded SMCs.
Consist of SMCs, elastin and collagen fibres arranged in highly
oraganised fashion.
At low and physiologic pressure, media is chief determinant of arterial
properties.

8. ADVENTITIA
 From EIL to ill defined boundary
continuous with the perivascular
connective tissue.
 Cells are more sparse and consist
mainly of fibroblast.
 Contains vasa vasorum and nerves.

9. Classification of Arteries
Classified according to cellular and fibrous components of media
1 Elastic arteries
 Well defined elastic lamellae and collagen fibres are prominent in media - Connective
tissue fibres are less frequent
 E.g arteries close to heart - aorta, brachiocephalic trunk, iliac arteries.
 Lamellar from heart units decrease to periphery.
2 Muscular arteries
 Primarily SMCs with fewer connective tissue.
 Nonparallel branching elastin strands increases capacity to change in diameter under
neuro humoral stimulation.
 e.g - femoral, popliteal, radial, ext carotid artery, etc

10. Veins
Venous system is adaptable with unique mechanism for accommodating hemodynamic stress
INTIMA
 One layer ECs sitting on incomplete elastic basement membrane
MEDIA
 Less developed than that of arterial system thus causing varicosities
 SMCs of this layer held in quiescent state
 Heparin like molecule neutralize FGF to downregulate cell proliferation.
 When vein exposed to arterial flow - increase cell proliferation
ADVENTITIA
 Thickest layer
 abundant collagen fibers
 Vasa vasorum is much more extensive compared with arteries

11. Venules
 Smallest of venous vessel, formed from confluence of several cappilaries
 10-50 um in diameter and 50 -650 um in length
 During inflammation - Main site for blood cell diapedesis and tissue exudate from circulation
to interstitial tissue
VENOUS VALVES
 Characteristic of small and medium sized vein- > 2mm dia.
 Local intimal semilunar infolding
 Reverse velocity of 30 cm/s – for valve closure
 Chronic venous insufficiency causing reduction in number

12. Artery Vein

13. Comparison of Vessel Walls

14. Lymphatics
 Initial lymphatics - single layer of ECs with large gap between cells and incomplete
basal lamina.
 Large lymph vessels – 3 concentric tunicae
 Valves in greater numbers
 Unidirectional flow network originating in the interstitial space Draining fluid from
ECM

15. Hemodynamics of Blood Vessels
Sheer Stress
 Endothelial Cells align in the direction of stress
 Greater the stress – more elongated cells.
 Redistribution of intracellular fiber quantity
 Higher stress – ECs express higher amount of stress fibers including actin, myocin and
other contractile proteins
Acute changes
 Release of vasoactive agents and alternation in vessel diameter
Chronic changes
 Enhance L- anginine / NO pathway
 Marked increase in NO synthase mRNA and cGMP
 NO and SOD anions help to activate MMP
 MMP induces remodeling IMP

16. Circumferential Stress
 Induce cell proliferation, In Endothelial cells
 Endothelin is released
 IncreasedTotal protein content and Gene expression
 SMCs hypertrophy
Shear Stress and circumferential stretch likely play a critical role in
determining loss and gain of vessel identity to adapt to each
environment.

17. Fundamentals of Atherosclerosis

18. Introduction
1. Disease of large and medium-sized muscular arteries
2. Characterized by – endothelial dysfunction, vascular inflammation, and the buildup of
lipids, cholesterol, calcium, and cellular debris within the intima of the vessel wall.
3. Intimal lesions called atheromas (also called Atheromatous or atherosclerotic
plaques), that protrude into vascular lumina.

19. Atheromatous Plaque
 A raised lesion with a soft, yellow, grumous core of lipid (mainly cholesterol and
cholesterol esters) covered by a firm, white fibrous cap.
 Plaques weaken the underlying media and can themselves rupture, causing acute
thrombosis.
 Primarily affects elastic, large and medium-sized muscular arteries
 In small arteries, atheromas can gradually occlude lumina, compromising blood flow and
cause ischemic injury.
 Causes acutely or chronically diminished arterial perfusion, such as mesenteric occlusion,
sudden cardiac death ,PAD etc

20. Theories of Pathogensis
1 Lipid Hypothesis:
 Hypercholestrolemia is associated with defective binding of LDL to cells
 Suppression of HMG CoA Reducatse fails as it depends upon the amount of
bound LDL
2 Monoclonal Hypothesis:
 Each atherosclerotic plaque is derived from single smooth muscle cell.
 This single cell acts as a precursor for clonal exoansion.

21. 3 Response to Injury Hypothesis:
 Endothelial Injury triggers Atheroma formation
 Injury maybe cause by mechanical disruption, exposure to toxic or infectious
agents, or endogenous inflammatory signals.
 Injury allows adhesion of platelets and an influx of LDL and other serum factors
into the subendothelial space.
 Platelets release their alpha granules and stimulate migration of SMC into the
intima, where they proliferate and form a thickened neointima responsible for
narrowing of the arterial lumen.
 Restoration of a healthy endothelial cell layer abates the process.

22.  Other investigators have countered that retention of
inflammatory lipids in the subendothelial space that
renders a particular area susceptible to atherosclerosis.
 This hypothesis is still under consideration.

23. Atheroma Formation

24. Atherosclerosis as Chronic
Inflammatory Disease
 LDL Retention
 Early attachment of Monocytes by oxidized LDL
 Members of the immunoglobulin superfamily (vascular cell adhesion molecule-1
[VCAM-1] and intercellular adhesion molecule-1 [ICAM]) cause more permanent
fixation
 Monocytes undergo a series of phenotypic modulations and become resident tissue
macrophages that take up oxidized LDL via the scavenger receptor A (SR-A) and
CD36.

25.  Proinflammatory mediators stimulate the migration of SMC from the tunica media
into the intima.
 Bone morphogenetic protein-2 (BMP-2) and inorganic phosphate induce the
osteochondrogenic phenotype in SMC leading to calcification.

26. Progression/Regression of Plaques
 Plaque formation is a dynamic process
 Periods of intermittent growth spurts are followed by relative
quiescence.
 Local non occlusive plaques induce healing process with cytokines and
growth factor production
 Acute plaque rupture with nonocclusive thrombosis may signal a
cascade of events leading to a fibrous atheroma and constrictive
remodeling.

27. Lifecycle of Antherosclerotic Plaque

28. Complications
 Vascular Stenosis
 Physical Disruption of Plaque
 Coronary/Carotid thrombosis
 Exposure of blood to eroded site of previous plaque accelerates thrombosis
 Most thrombotic complications lead to stenosis rather than complete
occlusion

29. Identification of Lesion
 Through impaired endothelial vasodilator function
 Molecular Imaging
 Contrast Enhance CT
 Contrast Enhanced Ultrasonography

30. Q & A

31. THANK YOU